Immune-based cancer therapies: mechanistic insights, clinical progress, and future directions.

Background

Cancer is a complicated and diverse illness that involves the uncontrolled proliferation of cells and the ability to invade or migrate to other areas of the body. It continues to be a major cause of illness and death globally [ 1 , 2 ]. The treatment landscape for cancer is diverse and continually evolving, encompassing various modalities aimed at eradicating malignant cells while minimizing damage to healthy tissues. Cancer treatment strategies have historically included surgery, chemotherapy, and radiotherapy, but recent advancements in immunotherapy have reshaped the therapeutic landscape [ 3 ]. Immunotherapy, a way of treating cancer that uses the body’s immune system to fight it, has greatly changed the field of cancer care in the last few years [ 4 , 5 ]. Unlike conventional therapies, immunotherapies primarily modulate the immune system’s ability to target and destroy cancer cells, although some, such as anti-programmed death-ligand 1 (PD-L1) inhibitors, directly target cancer cells. The natural ability of the immune system to identify and destroy cancer cells is instead enhanced or restored. This technique has demonstrated potential in the treatment of many forms of cancer and has several benefits, such as the possibility of achieving long-lasting remission and experiencing fewer adverse effects than traditional treatments do [ 6 – 8 ].

Immunotherapy encompasses several strategies, including immune checkpoint inhibitors, cancer vaccines, adoptive cell transfer, and cytokine therapies [ 9 , 10 ]. Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, inhibit proteins that prevent the immune system from fighting cancer cells. This makes immune reactions occur faster [ 11 – 13 ]. A person’s immune system is altered by adoptive cell transfer, making them more capable of identifying and eliminating cancer cells. Chimeric antigen receptor-T (CAR-T) cell treatment is an example that uses the above method [ 14 ]. The objective of cancer vaccines is to allow the immune system to react to certain cancer antigens. This helps the immune system find and fight cancer cells [ 15 ]. Chemicals such as interleukins and interferons are used in cytokine treatments to improve the ability of the immune system to fight cancer [ 16 , 17 ].

The response of cancer patients to immunotherapy is crucial. This signifies a fundamental change in the field of oncology, providing optimism for patients who have tumors that do not respond to traditional therapies. Several forms of cancer, such as melanoma [ 18 , 19 ], non-small cell lung cancer [ 20 ], and specific forms of leukemia and lymphoma [ 21 ], respond quite well to immunotherapy. Moreover, the development of combination therapies, where immunotherapy is used alongside other treatment modalities, is promising for enhancing treatment efficacy and overcoming resistance.

Despite its potential, immunotherapy has several challenges. The variability in patient responses, the development of resistance, and the potential for immune-related adverse effects are areas of active research and clinical concern [ 22 – 24 ]. However, the continuous progress in comprehending the processes of immune modulation and tumor immunology is creating opportunities for the development of more efficient and tailored immunotherapeutic approaches [ 25 ].

In addition, novel immunotherapeutic approaches are emerging. Personalized cancer vaccines, which are designed on the basis of the unique mutations present in an individual’s tumor, are being developed to improve the specificity and effectiveness of immune responses [ 26 ]. Bispecific antibodies, which can bind simultaneously to cancer cells and immune cells, are another promising innovation. These advancements aim to increase the precision and potency of immunotherapy, making it more effective for a broader range of patients [ 27 ].

This review aims to provide a comprehensive understanding of the role that immunotherapy has played in revolutionizing cancer treatment and to explore its potential to drive future advancements in oncology.

Types of cancer immune theraphy

Immune checkpoint inhibitors

Immune checkpoints are crucial regulatory pathways in the immune system that help maintain self-tolerance and prevent autoimmunity [ 28 ]. These pathways play crucial roles in controlling the duration and strength of immune responses, ensuring that the immune response can effectively respond to infections without causing substantial damage to the body's tissues. Cancer cells use different checkpoints in the body to evade detection and destruction by the immune system [ 29 ].

Mechanisms of action of immune checkpoint inhibitors

CTLA-4 pathway

One of the immunological checkpoint proteins that is produced on the surface of T cells is CTLA-4, which stands for cytotoxic T-lymphocyte antigen 4. It plays a crucial role in the process of suppressing immunological responses [ 30 ]. CTLA-4 competes with CD28, a stimulatory receptor on T cells, for binding to B7 molecules (CD80/CD86) on antigen-presenting cells (APCs). While CD28 binding to B7 molecules promotes T-cell activation and proliferation, CTLA-4 binding inhibits these processes. This inhibition is crucial for maintaining immune homeostasis and preventing autoimmunity [ 31 ]. However, in the context of cancer, the inhibitory function of CTLA-4 can be exploited by tumor cells to suppress antitumor immune responses, allowing them to grow and spread unchecked.

Anti-CTLA-4 antibodies, such as ipilimumab, block the interaction between CTLA-4 and B7 molecules [ 32 ]. These antibodies hinder the binding of CTLA-4 to B7, resulting in a decrease in the inhibitory signal and an increase in the stimulatory signal mediated by CD28. Consequently, there is an increase in the activation, reproduction, and endurance of T cells, enhancing the immunological reaction against malignant cells. Increased T-cell activity leads to the infiltration of tumors by stimulated T cells, hence facilitating the destruction of cancer cells [ 33 , 34 ].

Another important immunological checkpoint protein produced on the surface of T cells is called PD-1, which stands for "Programmed Death-1". Reduced T-cell activity results from an inhibitory signal transmitted when PD-1 binds to its agonists, PD-L1 and PD-L2. These ligands can be produced on cancerous cells or APCs [ 35 , 36 ]. This interaction results in a reduction in the generation of cytokines and a decrease in the ability of T cells to multiply and survive. By exploiting the PD-1 pathway, cancer cells can effectively "turn off" T cells, escaping immune surveillance and destruction. The PD-1 pathway is thus a major mechanism by which tumors create an immunosuppressive microenvironment [ 37 ].

PD-1 pathway

Anti-PD-1 antibodies (e.g., pembrolizumab and nivolumab) and anti-PD-L1 antibodies (e.g., atezolizumab) block the interaction between PD-1 and its ligands [ 38 ]. These antibodies restore T-cell activation and function by blocking this pathway, which in turn decreases inhibitory signals. This reactivation of T cells leads to enhanced recognition and destruction of tumor cells. Inhibiting the interaction between PD-1 and PD-L1 also leads to increased cytokine production, hence enhancing the fight of the immune system against cancer [ 39 , 40 ]. The mechanisms described are illustrated in Figure 1 , which shows the phases of T-cell activation and the immune response in cancer immunotherapy. Fig. 1 Mechanism of action of immune checkpoint inhibitors in cancer immunotherapy

Newer immune checkpoints: TIM-3, LAG-3, and TIGIT

The landscape of cancer immunotherapy has expanded significantly with the identification of newer immune checkpoints, including T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). These checkpoints provide critical insights into the complex mechanisms of immune regulation and resistance within the tumor microenvironment, representing promising therapeutic targets in the ongoing fight against cancer [ 41 ].

LAG-3

LAG-3 is another critical checkpoint that negatively regulates T-cell activation and proliferation. It is expressed on activated T cells, regulatory T cells (Tregs), and some antigen-presenting cells. LAG-3 binds to MHC class II molecules with a higher affinity than does CD4, effectively competing for binding and inhibiting T-cell activation [ 42 – 44 ]. Its role in T-cell exhaustion and immune suppression in the tumor microenvironment is well documented, as LAG-3 expression often correlates with poor clinical outcomes in various malignancies [ 45 – 47 ]. LAG-3 inhibitors are being developed as monotherapies and in combination with PD-1 inhibitors [ 48 , 49 ]. Early clinical trials have shown promising results, indicating that LAG-3 blockade can enhance T-cell function and improve responses to immunotherapy in cancers such as melanoma and non-small cell lung cancer. Researchers are also exploring the potential of combining LAG-3 inhibitors with other immunotherapeutic agents to overcome resistance mechanisms and improve overall survival rates [ 50 – 52 ].

TIGIT

TIGIT is a coinhibitory receptor expressed on T cells and natural killer (NK) cells that functions to dampen immune responses by inhibiting T-cell activation and promoting immune tolerance [ 53 ]. It competes with CD226 (also known as DNAM-1) for binding to shared ligands, such as PVR (poliovirus receptor) and Nectin-2, which are upregulated in many tumors [ 54 ]. The engagement of TIGIT results in the inhibition of cytotoxic T-cell activity and promotes the expansion of regulatory T cells, thereby fostering an immunosuppressive TME. Targeting TIGIT with monoclonal antibodies is an area of active research, with several trials underway evaluating its efficacy in various cancers, including hematologic malignancies and solid tumors [ 55 ]. Early studies suggested that combining TIGIT inhibitors with PD-1/PD-L1 inhibitors or other immunotherapeutic agents may enhance antitumor immunity and help overcome resistance to existing therapies. As clinical data emerge, understanding the optimal patient populations and treatment combinations will be critical for maximizing the benefits of TIGIT blockade in cancer therapy [ 56 ].

CAR-T-cell therapy

CAR-T (chimeric antigen receptor (CAR-T) cell) therapy is a groundbreaking form of adoptive cell transfer that significantly enhances the ability of a patient’s T cells to fight cancer [ 57 ]. This innovative therapy involves several intricate steps, starting with the collection of T cells from the patient’s blood. Once harvested, these T cells are genetically modified in a laboratory to express chimeric antigen receptors (CARs) on their surface. The unique capacity of T cells to identify and target cancer cells can be achieved through the use of CARs, which are synthetic receptors [ 58 , 59 ]. For T cells to attach to a particular antigen in cancer cells, the CAR structure incorporates an antigen-binding domain, which is usually obtained from a monoclonal antibody. Next, there is a hinge region that provides flexibility, a transmembrane domain that ensures a binding location in the cell's membrane, and intracellular signaling regions that play a vital role in T-cell activation and proliferation, such as CD3ζ and costimulatory domains such as CD28 or 4-1BB [ 60 , 61 ].

Following their modification, CAR-T cells are expanded in the laboratory before being reintroduced to patients. Cancer antigen-recognition T cells (CAR-T cells) bind to cancer cells expressing their target antigen, are activated, and then secrete cytotoxic substances that kill the cancer cells. The highly focused strategy has demonstrated exceptional efficacy in managing specific blood cancers, offering renewed optimism for individuals with previously resistant tumors [ 62 ]. This process is visually represented in Figure 2 , highlighting the step-by-step procedure of CAR-T-cell therapy. Fig. 2 This figure outlines the process of CAR-T-cell therapy, a personalized cancer treatment. The procedure involves five main steps: (1) acquiring T cells from the patient's blood, (2) genetically modifying the T cells to express chimeric antigen receptors (CARs), (3) expanding the number of CAR-T cells, (4) infusing the CAR-T cells back into the patient, and (5) allowing the CAR-T cells to recognize and attack cancer cells, leading to destruction of the tumor.

CAR construction

The CAR-T-cell therapy technique involves the extraction of T cells from the patient's bloodstream. These T cells subsequently undergo genetic modification under laboratory conditions to enable the expression of chimeric antigen receptors (CARs) on their cell surface. CARs are artificial receptors that give T lymphocytes the unique ability to selectively recognize and attack particular proteins found in cancer cells [ 63 ]. The construction of a CAR is a meticulous process, ensuring that each component functions synergistically to increase the efficacy of T cells against cancer. The initial component of a CAR's antigen-binding domain is its initial component. A monoclonal antibody is the usual source for this domain, which enables it to identify and attach to a particular antigen found on cancer cell surfaces. Precise binding specificity is essential for guiding CAR-T cells toward their intended targets and ensuring that they exclusively attack cancer cells, hence minimizing adverse effects on healthy organs. Following the antigen-binding domain is the hinge region, a flexible linker that provides the necessary mobility for the CAR to properly orient itself when engaging with the antigen. This flexibility is essential for the effective binding and subsequent activation of T cells [ 64 ].

Mechanism of action

Once equipped with CARs, T cells undergo a transformative process in CAR-T-cell therapy, aiming to combat cancer with precision and potency. Following genetic modification in the laboratory to express CARs, these T cells are cultivated to reach sufficient numbers for therapeutic effectiveness [ 65 , 66 ]. Moreover, patients typically undergo a preparative regimen, often involving chemotherapy, which serves to reduce the existing population of lymphocytes and create space for incoming CAR-T cells upon reintroduction into the bloodstream [ 67 ]. The therapeutic mechanism of CAR-T cells is executed via a sequence of carefully coordinated procedures. After being reintroduced into the body, CAR-T cells travel through the bloodstream and aggressively search for cancer cells that have a particular antigen targeted by the CARs. The antigen-binding domain of the chimeric antigen receptor (CAR) plays a crucial role in this stage, allowing CAR-T cells to identify and attach to the antigen on the outer layer of cancer cells with exceptional precision. Upon binding to their specific antigen, CAR-T cells activate an internal signaling cascade via their CD3ζ and costimulatory regions (such as CD28 or 4-1BB), which leads to their activation. This activation triggers rapid and extensive multiplication of CAR-T cells, resulting in a significant increase in their quantity. This increase helps generate a strong and effective immune system defense against malignancy. The cytotoxic process is a crucial component of CAR-T-cell therapy. Upon encountering cancer cells, activated CAR-T cells produce cytotoxic granules that contain perforin and granzymes. These molecules can penetrate cancer cells, inducing apoptosis or programmed cell death. Furthermore, CAR-T cells secrete cytokines such as interferon-gamma and interleukins, which enhance the overall efficacy of therapy by amplifying the immune response and recruiting additional immune cells to the tumor location. The sustained immune response generated by CAR-T cells ensures continued surveillance and destruction of cancer cells bearing the targeted antigen. This prolonged activity offers a potential advantage over conventional therapies by potentially achieving durable remission in patients with otherwise treatment-resistant cancers. Ongoing research continues to refine CAR-T-cell therapy and explore improvements in efficacy, safety, and applicability across various cancer types, promising further advancements in personalized cancer treatment strategies.

Evolution of CAR-T-cell development

The advancements in CAR development over the last thirty years can be broadly categorized into five generations on the basis of the structure and composition of the endodomain. The initial generation of CARs comprises a solitary CD3ζ intracellular domain [ 68 ]. Preliminary investigations with first-generation CAR-T cells demonstrated diminished cytotoxicity and proliferation due to insufficient costimulatory (e.g., CD27, CD28, CD134, and CD137) and cytokine (e.g., interleukin (IL)-2) signaling [ 68 , 69 ]. A second generation of CARs was developed to improve T-cell proliferation and cytotoxicity by incorporating a costimulatory domain, such as portions of CD28 or CD137, into the intracellular signaling domain [ 70 – 72 ]. The third generation of CARs enhanced the second generation by including a third intracellular signaling sequence with an extra costimulatory domain, such as CD134 or CD137 [ 68 ]. The fourth generation of CARs is derived from second-generation CARs and incorporates a protein, such as interleukin 12 (IL-12), which is expressed either constitutively or inducibly following CAR activation. T cells modified with these fourth-generation CARs are designated T cells redirected for universal cytokine-mediated killing (TRUCKs). The activation of these CARs enhances the production and release of target cytokines to facilitate tumor eradication through many synergistic processes, including exocytosis (perforin, granzyme) and death ligand–death receptor (Fas–FasL, TRAIL) pathways [ 73 ]. TRUCKs will be addressed in a subsequent section. A fifth generation of CARs is presently under investigation; these are derived from the second generation of CARs, which incorporate a shortened cytoplasmic IL-2 receptor β-chain domain with a binding site for the transcription factor STAT3. The antigen-specific activation of this receptor concurrently initiates TCR signaling (via the CD3ζ domains), costimulatory signaling (CD28 domain), and cytokine signaling (JAK–STAT3/5), thereby delivering the three synergistic signals necessary for complete T-cell activation and proliferation [ 72 ]. Further versions of the previously mentioned CARs, including dual CARs, split CARs, and inducible-split CARs, have been developed to augment the specificity and regulation of the transfused T cells. The CARs will be elaborated upon in further depth below. Figure 3 shows the structures of different chimeric antigen receptor (CAR) generations. Fig. 3 Structures of different chimeric antigen receptor (CAR) generations. [ 74 ]

Over the past thirty years, CARs have evolved from their initial characterization to receiving FDA approval for patient usage. Despite these advancements, the innovative CAR designs and enhancements shown in recent generations, as demonstrated in vitro or in animal models, have not been validated in human patients. No study has yet conducted a clinical comparison of first- or subsequent-generation CARs targeting a single antigen, hindering an accurate assessment of the various CAR generations and complicating the selection of appropriate combinations for future clinical studies. Consequently, the evaluation of a specific CAR generation relies on preclinical animal models rather than clinical evidence. At present, it is uncertain which design yields the optimal clinical benefit for patient outcomes.

Adoptive Cell Therapy in Cancer Immunotherapy

Adoptive cell therapy (ACT) is a cutting-edge approach in cancer immunotherapy in which immune cells are extracted, modified, and reinfused into patients to target tumors. The key types of ACT include CAR-T, TCR-T, CAR-NK, and CAR-M therapies.[ 75 ]

TCR-T (T-cell receptor-engineered T cell) therapy

TCR-T-cell therapy is another promising form of adoptive cell therapy that differs from CAR-T-cell therapy in that it focuses on the natural mechanism of T-cell recognition. TCR-T cells are engineered to express T-cell receptors (TCRs) that can recognize tumor-specific antigens presented by patients’ MHC molecules. This allows TCR-T cells to target a broader range of tumor antigens, including intracellular proteins, which are inaccessible to CAR-T cells [ 76 ]. TCR-T-cell therapy is particularly useful for targeting tumors that express specific shared antigens, such as NY-ESO-1 or MART-1, which are commonly found in cancers such as melanoma and sarcoma [ 77 ]. However, the dependency on MHC means that TCR-T cells are limited by the patient's HLA type, and variations in antigen presentation can affect treatment efficacy. Additionally, tumors can evolve to downregulate MHC expression as an immune evasion mechanism, limiting the long-term effectiveness of TCR-T-cell therapy. Despite these challenges, TCR-T-cell therapy holds great promise, particularly in the treatment of solid tumors where CAR-T cells have struggled [ 78 , 79 ].

CAR-NK (chimeric antigen receptor natural killer) cell therapy

CAR-NK therapy is an emerging form of adoptive cell therapy that leverages the innate immune capabilities of natural killer (NK) cells. Like CAR-T cells, CAR-NK cells are engineered to express a CAR that allows them to specifically target tumor antigens [ 80 ]. However, NK cells have the unique ability to kill tumor cells without prior sensitization and do not rely on MHC recognition, making them more versatile in targeting a wide range of cancers. Additionally, CAR-NK cells have a lower risk of causing severe side effects, such as cytokine release syndrome (CRS) and graft-versus-host disease (GVHD), which are common concerns with CAR-T-cell therapy [ 81 ]. This reduced risk makes CAR-NK cells potentially safer, and they can be derived from both autologous (patient-derived) and allogeneic (donor-derived) sources, suggesting the possibility of "off-the-shelf" treatments. Early clinical trials have shown encouraging results in treating B-cell malignancies, particularly in targeting CD19-positive cancers, and ongoing research is exploring their application in solid tumors as well. CAR-NK therapy represents a promising alternative or complement to CAR-T-cell therapy, particularly for patients who may not be candidates for T-cell-based therapies [ 82 ].

CAR-M (chimeric antigen receptor macrophage) therapy

CAR-M therapy is a novel and still-developed form of adoptive cell therapy that modifies macrophages to recognize and attack cancer cells. Macrophages, as part of the innate immune system, play a critical role in phagocytosis (engulfing and digesting pathogens or dead cells) and can also present tumor antigens to other immune cells, promoting a broader immune response [ 83 ]. An issue with CAR-macrophage-based therapy is that macrophages can phagocytize only portions of targeted cells. To mitigate this constraint, the combination of an anti-CD47 antibody and CAR-T cells was used to enhance the phagocytosis of whole cells [ 84 ]. Another technique involves the engulfment of receptor intracellular domains into the CAR construct to initiate the engulfment of whole cells. For example, a CAR incorporating Megf10 and the ɣ component of Fc receptors (chimeric antigen receptor-phagocytes, CAR-Ps) was designed for macrophages to initiate phagocytosis of cells expressing particular antigens. Additionally, CAR-Ps are associated with the PI3K p85 subunit to create a "tandem" CAR (CAR-Ptandem) capable of efficiently engulfing human cancer cells [ 85 ].

Cancer vaccines

As a state-of-the-art strategy in oncology, cancer vaccines target cancer cells by directing the body's immune system to destroy them. These vaccines are designed to stimulate the immune system to fight against antigens that are specific to cancer cells. They have the potential to be used for both preventing and treating cancer [ 86 ].

Types of cancer vaccines

Cancer vaccines can be classified into two main categories: preventative and therapeutic. Every iteration of treatment seeks to use the immune system's capacity to identify and eradicate cancerous cells; however, their methodologies and desired results vary [ 87 ].

Preventive vaccines

Preventive cancer vaccines are designed to prevent cancer development by targeting specific viruses or pathogens known to cause cancer. The most notable example of a preventive cancer vaccine is the human papillomavirus (HPV) vaccine. HPV is a common virus that can lead to cervical cancer, as well as other cancers, such as anal, vaginal, vulvar, penile, and oropharyngeal cancers [ 88 , 89 ]. HPV vaccination functions by stimulating the immune system to fight against the virus, preventing HPV infection and the consequent formation of malignancies linked to HPV. Other examples of preventive cancer vaccines may target viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV), which can lead to liver cancer (hepatocellular carcinoma) [ 90 ]. These vaccinations successfully lower the chance of developing specific types of cancer by avoiding viral infections that are associated with cancer development. This strategy for cancer prevention is proactive. Three FDA-approved vaccines are available to protect against HPV infection: Gardasil 9 and Cervarix.Gardasil was the first HPV vaccine approved in 2006 [ 91 ].

Therapeutic vaccines

In contrast, therapeutic cancer vaccines are designed to treat existing cancers by stimulating the immune system to recognize and attack cancer cells that express specific antigens. These vaccines aim to enhance the body's natural immune response against cancer cells, potentially slowing disease progression or inducing remission. A therapeutic cancer vaccine functions by stimulating the immune system to target cancer cells through the introduction of specific antigens exclusive to tumors [ 92 ]. These antigens can originate from proteins or other substances that are produced only by cancer cells. Therapeutic vaccines commonly incorporate adjuvants, which are chemicals that stimulate and augment the immunological response to the antigen, to increase immune activity. Dendritic cells and other antigen-presenting cells (APCs) are known to play important roles in the development of therapeutic vaccines [ 93 ]. They collect and analyze antigens that are specific to cancer and then present these antigens to T cells in a manner that stimulates them to identify and destroy cancerous cells throughout the entire body. Initiating a targeted and long-lasting immune response against cancer is the goal of this therapy, which has the potential to reduce or eradicate the tumors shown in Figure 4 . One notable example of a therapeutic cancer vaccine is Sipuleucel-T (Provenge), which is approved for the treatment of metastatic castration-resistant prostate cancer. Sipuleucel-T is a procedure in which a patient's dendritic cells are collected and then exposed to a prostate cancer-specific antigen (PAP) that is combined with an immune-stimulating agent called granulocyte‒macrophage colony‒stimulating factor (GM-CSF). After being activated, these dendritic cells, which are loaded with antigens, are reintroduced into the patient's body. They then trigger a specific immune response against prostate cancer cells that express PAP [ 94 , 95 ].

Various types of therapeutic vaccines are being developed, including peptide vaccines, cell-based vaccines, mRNA vaccines, and DNA vaccines. Each of these approaches has unique mechanisms and advantages, as well as challenges that researchers are actively addressing.

Peptide vaccines

Peptide vaccines consist of short sequences of amino acids (peptides) that correspond to specific tumor-associated antigens (TAAs) or neoantigens. By presenting these peptides to the immune system, the vaccine aims to elicit a targeted immune response against cancer cells expressing those antigens. Peptide vaccines can be customized on the basis of the individual patient’s tumor profile, which enhances their specificity and potential effectiveness. A notable example is the peptide vaccine targeting prostate-specific antigen (PSA), which is used in patients with prostate cancer. While peptide vaccines have shown promise in clinical trials, challenges remain in achieving robust and durable immune responses, as well as in identifying suitable antigens for different cancer types [ 96 ].

Cell-based vaccines

Cell-based vaccines, including dendritic cell vaccines and whole tumor cell vaccines, leverage the ability of immune cells to activate and educate the immune system against cancer. Dendritic cell vaccines involve isolating dendritic cells from patients, loading them with tumor antigens, and reinfusing them to stimulate T-cell activation [ 97 ]. Whole tumor cell vaccines are derived from a patient’s own tumor cells or genetically modified tumor cells that express antigens to provoke an immune response. These approaches have the advantage of presenting a broad array of antigens to the immune system, potentially overcoming the limitations of single-antigen targeting [ 98 ]

mRNA vaccines

mRNA vaccines represent a cutting-edge approach to cancer immunotherapy. These vaccines use messenger RNA (mRNA) to instruct cells to produce specific tumor antigens, thereby eliciting an immune response. The mRNA can be delivered in lipid nanoparticles, which facilitate their cellular uptake. Notably, mRNA vaccines have gained significant attention because of their rapid development during the COVID-19 pandemic and are now being explored in oncology [ 99 ]. Personalized mRNA vaccines can be designed on the basis of individual tumor sequencing, allowing for the targeting of patient-specific neoantigens. Early clinical trials have shown promise in various cancers, including melanoma and non-small cell lung cancer, but further research is needed to optimize their efficacy and assess long-term responses [ 100 , 101 ].

DNA vaccines

DNA vaccines involve the direct introduction of plasmid DNA encoding tumor-associated antigens into the body. Once inside, the host cells use DNA to produce the corresponding antigens, triggering an immune response against the tumor. This approach is appealing because of its stability and ease of production. DNA vaccines can be designed to target specific cancer antigens and may be delivered via intramuscular injection or electroporation to increase uptake. While DNA vaccines have shown potential in preclinical studies and early-phase clinical trials, challenges remain in ensuring sufficient immune activation and overcoming potential tolerance mechanisms [ 102 , 103 ]. Fig. 4 Dendritic cell-based immunotherapy for prostate cancer

Cytokine Therapies in Cancer Treatment

Cytokine therapies employ signaling proteins called cytokines, which have essential functions in controlling immune responses, to increase the body's natural defenses against cancer. Interleukins (ILs) and interferons (IFNs) are crucial cytokines employed in cancer therapy [ 104 ]. These cytokines possess unique modes of action and are utilized to treat different types of tumors.

Interleukins (ILs) and interferons (IFNs) are pivotal cytokines employed in cancer therapy because of their potent immunomodulatory properties. IL-2 and IFN-α are among the most extensively studied and utilized cytokines in oncology [ 105 ]. Interleukin-2 (IL-2) plays a critical role in promoting the proliferation and activation of T cells and natural killer (NK) cells. By binding to IL-2 receptors on these immune cells, IL-2 enhances their cytotoxic activity against cancer cells. Owing to the ability of this cytokine to increase the number of effector T cells, which can selectively recognize and target cancer cells, the immunological response of the body to tumors is strengthened [ 106 , 107 ]. Interferon-alpha (IFN-α) has multiple effects on cancer therapy. It improves dendritic cell antigen presentation, which helps T lymphocytes recognize cancer cells. The capacity of NK cells and macrophages to destroy cancer cells is increased by IFN-α, which also increases their cytotoxic activity. Furthermore, IFN-α has direct antiproliferative effects on cancer cells, inhibiting their growth and replication [ 108 ].

Mechanism of action

IL-2 and IFN-α work in different ways, but they both improve therapy by increasing the ability of the immune system to detect and destroy cancer cells. IL-2 primarily acts by stimulating T-cell and NK cell proliferation and activation, whereas IFN-α enhances immune surveillance and antitumour immunity through multiple pathways, including increased cytotoxicity and inhibition of tumor proliferation. IL-2 has been utilized in the treatment of metastatic renal cell carcinoma and metastatic melanoma. In metastatic renal cell carcinoma, IL-2 therapy has demonstrated durable responses in a subset of patients, particularly those with good performance status and limited disease burden. Similarly, IL-2 has shown efficacy in the treatment of metastatic melanoma, where it enhances immune-mediated tumor regression. IFN-α is used to treat many types of malignancies, such as melanoma and certain leukemias. IFN-α therapy has been utilized as an adjuvant treatment for melanoma to decrease the likelihood of recurrence after surgical removal. The ability of IFN-α to modulate immune responses and inhibit tumor cell proliferation makes it a valuable component of treatment regimens for certain hematologic malignancies as well [ 109 , 110 ].

Oncolytic viruses

Oncolytic viruses are a promising frontier in cancer therapy, leveraging the natural ability of viruses to selectively infect and destroy cancer cells while leaving healthy cells intact. This innovative approach involves the use of genetically modified or naturally occurring viruses that have been engineered to specifically target and replicate within cancerous tissues [ 111 ]. The mechanism of action of oncolytic viruses begins with their selective entry into cancer cells, facilitated by specific receptors or vulnerabilities present on the surface of these cells. Once inside the cancer cell, the virus hijacks the cellular machinery to replicate, leading to the production of viral progeny. As infected cancer cells are filled with newly synthesized viruses, they eventually burst (lyse), releasing viral particles that can infect neighboring cancer cells. This process not only directly destroys cancer cells but also stimulates an immune response against the tumor. A viral infection within the microenvironment of a tumor results in the production of threat indicators and viral antigens, which in turn alerts the immune system to recognize and destroy cancer cells located throughout the body [ 112 , 113 ].

Several types of viruses, including adenoviruses, herpes simplex viruses (HSVs), reoviruses, and vaccinia viruses, have been investigated for their oncolytic potential. Each virus type has unique characteristics that can be exploited for therapeutic purposes, such as its ability to infect specific types of cancer cells or its potential for genetic modification to increase tumor specificity and efficacy. Oncolytic viruses have demonstrated encouraging outcomes in clinical studies for a range of malignancies, including pancreatic cancer and glioblastoma, among others. These viruses are often administered directly into the tumor or intravenously, and they may be used alone or in combination with other cancer therapies, such as chemotherapy or immune checkpoint inhibitors, to maximize treatment efficacy [ 114 , 115 ]. Challenges in the field include optimizing viral delivery, minimizing potential side effects and overcoming immune responses that can clear the virus before it reaches all tumor sites. Current research is continuously improving the utilization of oncolytic viruses, intending to broaden their usage in many types of cancer and enhancing patient outcomes by leveraging the potential of viruses to combat cancer in a precise and efficient way [ 116 ].

Mechanisms of action of oncolytic viruses

Oncolytic viruses exert their anticancer effects through several key mechanisms of action that selectively target and destroy tumor cells while sparing normal tissues. First and foremost, these viruses are engineered or naturally evolve to preferentially infect cancer cells, often due to specific vulnerabilities in the tumor's cellular machinery or signaling pathways. Upon entering a cancer cell, the virus begins to replicate, exploiting the host cell's resources. This replication process culminates in cell lysis, leading to the release of new viral particles and the subsequent spread of the virus to neighboring cancer cells. As infected cells die, they also release tumor-associated antigens and proinflammatory cytokines, which help stimulate an immune response against the tumor. This immune activation is a critical aspect of oncolytic virotherapy; the presence of viral antigens can increase the visibility of the tumor to the immune system, prompting an attack not only on virus-infected cells but also on surrounding cancer cells that may not have been directly infected by the virus. Additionally, oncolytic viruses can induce immunogenic cell death (ICD), which further amplifies the immune response by promoting the maturation of dendritic cells and the activation of T cells. Furthermore, oncolytic virotherapy can be effectively combined with other treatments, such as checkpoint inhibitors or other immunotherapies, to enhance the overall antitumor effect, thereby maximizing therapeutic outcomes. Overall, the multifaceted mechanisms of oncolytic viruses make them promising approaches in the landscape of cancer immunotherapy, leveraging both direct oncolysis and immune system activation to achieve a more comprehensive attack on tumors [ 117 ].

Bispecific Antibodies and Their Mechanism of Action

Bispecific antibodies (BsAbs) are engineered immunotherapeutic agents that possess the unique ability to bind simultaneously to two different antigens or epitopes. This dual targeting ability allows them to bridge distinct cellular populations, increasing their therapeutic efficacy in the treatment of various diseases, particularly cancer [ 118 ]. BsAbs are designed to engage both immune effector cells, such as T cells or natural killer (NK) cells, and tumor cells, thereby promoting immune-mediated attack on tumors. The primary mechanism of action for bispecific antibodies involves the recruitment and activation of T cells. By binding to a specific tumor-associated antigen (TAA) on the surface of cancer cells and simultaneously engaging the CD3 receptor on T cells, BsAbs effectively redirect T cells to the tumor site. This interaction activates T cells, prompting them to proliferate and release cytotoxic molecules such as perforin and granzymes, leading to the destruction of targeted cancer cells [ 119 , 120 ]. For example, bispecific T-cell engager (BiTE) antibodies, such as blinatumomab, target CD19 in B-cell malignancies and CD3 in T cells, demonstrating significant antitumor activity in diseases such as acute lymphoblastic leukemia (ALL) [ 121 , 122 ]. In addition to T-cell engagement, some bispecific antibodies are designed to target both tumor antigens and immune checkpoint receptors, effectively combining direct tumor targeting with immune modulation. By inhibiting immune checkpoints, these BsAbs can further enhance T-cell activation and sustain antitumor responses.

Moreover, bispecific antibodies can be engineered to utilize different mechanisms of action depending on their structure and design. For example, some BsAbs can engage NK cells, macrophages, or other immune cells to exert their effects [ 123 ]. This versatility allows for tailored approaches in therapy, providing opportunities to enhance immune responses against various tumor types. Despite their potential, the clinical application of bispecific antibodies is not without challenges. Issues such as manufacturing complexity, the potential for immunogenicity, and the need to optimize dosing regimens require ongoing research and development [ 124 , 125 ]. Nonetheless, bispecific antibodies represent a promising frontier in cancer immunotherapy, leveraging the power of the immune system to achieve targeted and effective antitumor responses.

Recent advances in delivery modalities for cancer immunotheraphy

The development of cancer immunotherapies that are both effective and safe for host cells depends on the development of delivery systems that are both efficient and effective (Figure 5 ). When developing a cancer treatment, it is necessary to consider a wide range of factors, including dosing, the manufacturing process, homing, degradation, and delivery. Physiochemical and biological factors should be considered throughout the drug development and delivery process. Table 1 shows the different ways in which cancer immunotherapy medicines can be delivered. Fig. 5 Multifaceted Approaches in Cancer Immunotherapy

Table 1 Delivery techniques for cancer immunotherapy [ 126 ] Delivery Technology Types/Source Cargo Cancer Type Reference Liposomes ErbB2/HER2 peptide Renal carcinoma [ 127 ] OVA Thymoma [ 128 ] ACT-cell-specific antibodies and Interleukin-2 (IL-2) Melanoma [ 129 ] Plasmid encoding telomerase-specific oncolytic adenovirus Colorectal cancer [ 130 ] Polymer OVA and Hydroxychloroquine Thymoma [ 131 ] PLK1 inhibitor and PD-L1 antibody NSCLC [ 132 ] IR780 and PD-L1 antagonist Colorectal cancer [ 133 ] Nanoparticles Dendrimer PD-L1 siRNA and IL-2 encoding plasmid DNA HCC [ 134 ] Inorganic nanocarriers Vesicular stomatitis virus Colorectal cancer [ 135 ] Adenovirus Pancreatic cancer, Colorectal cancer [ 136 ] mRNA-encoding OVA and R848 Melanoma [ 137 ] RNA/DNA Technology Anti-PD-1 antibody and CpG oligodeoxynucleotides Melanoma [ 138 ] OVA Melanoma [ 139 ] Nanovaccine Peptide neoantigen (Adpgk) and R848 and CpG Colorectal cancer [ 140 ] cyclic dimeric guanosine monophosphate (CDG) Melanoma [ 141 ] Heterologous administration of HPV16 E7 epitope-loaded nanocomplexes inhibits tumor growth in mouse model Melanoma [ 142 ] Extracellular Vesicles Dendritic cells VEGF siRNA Breast cancer [ 143 ] Bone Marrow-Derived MSC TRAIL Lung Cancer [ 144 ] A549 Lung Carcinoma cells (Human) Doxorubicin Lung carcinoma [ 145 ] B16-F10 melanoma cells (Mouse) CpG DNA Melanoma [ 146 ] H22 Hepatocarcinoma cells (Mouse) Doxorubicin, 5-FU Hepatocarcinoma [ 147 ] Exosomes Let-7a miRNA Breast cancer [ 148 ] EGFR nanobodies Epidermal [ 149 ] Cisplatin Ovarian cancer, Hepatocarcinoma [ 150 ] Implantable Scaffolds Collagen and HA cross-linking scaffold GEM, poly(I) Breast cancer [ 151 ] PLG scaffold GM-CSF, CpG-ODNs Melanoma [ 152 ] Hyaluronic acid scaffold CAR-NK cells Breast cancer [ 153 ] Injectable Scaffolds Alginate Hydrogel Celecoxib, PD-1 antibody Melanoma, Breast cancer [ 154 ] PEGylated poly(L-valine) hydrogel TCL, poly(I) Melanoma [ 155 ] ROS-degradable hydrogel GEM, PD-L1 antibody Melanoma, Breast cancer [ 156 ] Cell-Based Delivery Erythrocyte Curcumin Liver cancer [ 157 ] Glucose oxidase, Tirapazamine Colon cancer [ 158 ] DOX Lymphoma [ 159 ] Cytotoxic T cells Taxol Gastric cancer [ 160 ] NK cell TCPP Breast cancer [ 161 ] Car-T Cells - Glioblastoma, hepatic colorectal metastases, peritoneal carcinomatosis, pleural mesothelioma, mesothelioma [ 162 ]

Nanoparticle-based cancer immunotherapy

As useful additives in cancer immunotherapy, nanomaterials provide several advantages, such as a high surface-to-volume ratio, photodynamics, electrical and magnetic conductivity, optical absorption, and fluorescent behavior [ 163 ]. The application of nanomedicine-based drug delivery systems has attracted interest because of their biocompatibility, drug transport capabilities, ability to offer continuous drug release in cancer immunotherapy techniques, and current technological breakthroughs in nanoparticles [ 164 ]. A robust delivery platform that can traverse the intricate structure around the tumor is necessary to circumvent the obstacles to drug delivery to the tumor microenvironment [ 165 ]. Novel approaches to cancer immunotherapy, such as drug delivery via nanoparticles, hold great promise [ 166 ].

Researchers are exploring methods to provide therapies to tumors, as nanoparticles can selectively target cancer cells [ 167 ]. Enhancing the distribution and localization of medication within tumors can be accomplished by employing nanoparticle-based delivery systems that target tumors [ 168 ]. Exosomes, polymers, dendrimers, and inorganic nanocarriers are among the many platforms that nanoparticles use to transport proteins, inflammatory compounds, peptides, and small molecules [ 169 ].

The duration of drug accumulation in the tumor microenvironment is controlled by a crucial nanoparticle characteristic called enhanced permeability and retention (EPR) [ 170 ]. The ability of the immune system to target cancer cells is diminished when tumor-associated antigens elicit an immunological response with reduced anticancer effectiveness. When combined with a nanodelivery system, they are efficiently protected from degradation and can connect with antigen-presenting cells. This relationship stimulates cytotoxic T cells, which possess a potent anticancer function.

Copolymer micelles have demonstrated enhanced permeability and retention (EPR) effects when employed for tumor targeting. The copolymerization of polylactic acid and carboxymethyl cellulose, followed by modification with an anti-EpCAM antibody, can be utilized to selectively deliver the chemotherapeutic drug doxorubicin to hepatic cells (HepG2). The chemical doxorubicin was specifically released at the tumor location, and the modified drug-loaded micelles exhibited anticancer properties in both laboratory and live circumstances [ 171 ].

Nanofibers made of polylactic-co-lactic glycolic acid enhanced apoptosis and suppressed colon cancer, according to research by Badrinath et al. [ 172 ]. A study conducted by Chiang et al. demonstrated the successful eradication of tumors in a mouse model of 4T1 breast cancer via the use of a combination of anti-PDL1 checkpoint inhibitors and T-cell-activating drugs. This allows them to activate immune cells and eliminate tumors. IO@FuDex3 nanocomplexes were formed via conjugation with functionalized fucoidan-dextran and superparamagnetic iron oxide nanoparticles [ 173 ]. One further approach to target tumors involves the use of magnetic nanoparticles. This can be achieved in several ways, including changing the tumor environment, activating antigen-presenting cells (APCs), polarizing macrophages, stimulating T cells, and delivering natural killer (NK) cells [ 174 ].

A different study revealed that by combining a fluoropolymer with the antigen ovalbumin, dendritic cells can mature and present antigens more effectively, leading to tumor suppression. Cancer recurrence and metastasis are prevented by combining these fluoropolymers with antigens obtained from primary cancer cell membranes that have been surgically removed [ 175 ]. In their study on colon cancer and melanoma, Luo et al. demonstrated that neoantigen-based immunotherapy was effective and had visible effects. Researchers reported that nanovaccination effectively inhibited the growth of tumors and increased survival rates in a live animal model. In their study, Luo et al. reported that neoantigen-based immunotherapy effectively treated colon cancer and melanoma, and it also had observable effects. Researchers reported that nanovaccination effectively inhibited the growth of tumors and increased the rate of survival in a live animal model [ 176 ].

Various techniques have been employed to combine inorganic and organic nanoparticles to create highly efficient photothermal substances for the eradication of cancer cells [ 177 , 178 ]. Gold nanoparticles were initially utilized for nanoparticle manufacturing because of their biocompatibility and optical characteristics. However, their limited effectiveness in photothermal therapy has led to the modification of their surface by coating them with silica. In laboratory studies, the resulting cluster of silica-coated gold nanoparticles effectively promoted photothermal transcription in prostate cancer cells. Within fifteen days, the malignancies had completely disappeared [ 179 ]. Alternatively, the immune system's response to cancer could be enhanced by the use of micrometal organic frameworks (MOFs) loaded with anti-DEC205 antibodies. In this investigation, sonodynamic immunotherapy was used to functionalize AMR-MOF@AuPt via ultrasonic-based deep-tissue-penetrating sonication. As a result, a substantial amount of reactive oxygen species are produced, leading to the successful elimination of cancerous cells and distant metastases [ 180 ].

Biomaterial-based cancer immunotherapy

Biomaterial-based delivery systems are characterized by low invasiveness, precise targeting, regulated release, strong effectiveness, activation of immune cells, and low toxicity. These traits make them a promising strategy for cancer immunotherapy [ 172 , 181 ]. To generate anticancer activity, implantable and injectable biomaterials based on scaffolds and nanomaterials are commonly used [ 182 ].

A cancer vaccine has been shown to increase the immune response against tumors by reducing immune suppression in the tumor microenvironment. This is achieved via the use of tumor lysate-based antigens, nano adjuvants that express Toll-like receptor (TLR 3 agonist), and gemcitabine, which eliminates myeloid-derived suppressor cells (MDSCs) [ 151 ]. Ren et al. employed a methacrylate hyaluronic acid implantable scaffold that is biodegradable and changeable in terms of its macroporous structure. Many chemicals—PTX, an antigen-presenting cell activator, R837, and compounds that inhibit immunological checkpoints—have been added to this scaffold. After that, a mouse model with 4T1 breast tumors was used to implant this scaffold. Increased numbers of antigen-presenting cells (APCs), decreased numbers of myeloid-derived suppressor cells (MDSCs), and increased numbers of M2 macrophages are among the outcomes of the immune response against cancer [ 183 ]. A three-dimensional synthetic hyaluronic acid scaffold was created by Ahn et al. This scaffold improved the efficacy against breast cancer in a surgically removed tumor model by increasing mRNA production, cytokine release, and tumor elimination [ 153 ].

Because different biomaterials have varied strengths in different contexts, the choice between injectable and implantable designs is often based on the specific requirements of the application. A less invasive alternative to surgical implantation is the direct injection of implantable materials into tissues or organs. This technique lessens the inflammatory response and tissue damage that are common in wounds [ 184 ]. Cryogels, hydrogels, and self-assembling systems are only a few examples of the natural and synthetic components that can be used to create injectable biomaterials [ 185 ]. A supramolecular hydrogel was created by Liu et al., which can be used as both an ICD and a therapeutic agent for immune checkpoint inhibitors. It is designed to be delivered locally and has dual activity [ 186 ].

Extracellular vesicles

Extracellular vehicles (EVs) are small membranous structures that result from the fusion of the plasma membranes of cells and endosomes inside the cell. These structures are then released into the extracellular space. Every day, studies are uncovering the potential of EVs in delivering medications specifically to cancer cells, making them a promising drug delivery technique [ 187 , 188 ]. Complex membranous EVs preferentially enter cells by passing via tight junctions [ 189 ]. To target a liver malignancy, Wang et al. used exosomes as a delivery mechanism. Because of its poor solubility, PTX has limited therapeutic efficacy; nonetheless, it has been incorporated into exosomes to increase its potential. With this method, tumor preservation and inhibition were both shown to be more effective [ 190 ]. The production of exosomes by dendritic cells with cancer antigens and functional major histocompatibility complexes (MHCs) was reported by Zitvogel et al. These findings revealed that these exosomes could initiate the neutralization of tumors by cytotoxic T lymphocytes (CTLs) [ 191 ]. Researchers have used curcumin-loaded exosomes to treat malignant glioma in brain tissue in a live mouse model by penetrating the blood‒brain barrier [ 192 ].

T-cell Therapy Delivery Methods

Recent developments in technology have made it possible to isolate, genetically modify, and cultivate T cells externally from a patient's blood via T-cell-based treatments at the top of the field of cancer immunotherapy [ 193 ]. By modifying T-cell receptors and introducing cancer-infiltrating lymphocytes (TILs), the body can produce particular antigens and HLAs, which destroy cancer cells [ 194 ].

With respect to blood cancers, adoptive cell therapy—specifically T-cell therapy—is second to none. Patients in the US can now receive therapy with CAR-T cells, a therapy that has recently received multiple FDA approvals, for a range of B-cell malignancies. This therapy involves collecting patient blood and modifying T cells to specifically target and treat these types of cancers. While this technique has proven to be effective against blood cancers, its efficacy against solid tumors is limited owing to inadequate penetration into the intricate tumor microenvironment. As a result, researchers are always looking for a better way to deliver CAR-T-cell therapies to cancer cells [ 195 ]. Local injection or implanted bioscaffold administration has been successful, and long-term distribution inside the cancer microenvironment has improved with parallel administration of CAR-T cells with immunostimulatory molecules. To demonstrate this point, a mouse model was used by Grosskopf AK et al. to administer IL-15-loaded CAR-T cells via a polymer‒nanoparticle (PNP) hydrogel. This method allows for the delivery of cells both near and far from tumors, potentially enabling the treatment of solid tumors and achieving a cure [ 196 ].

Moreover, employing multiple treatment techniques may improve the efficacy of solid tumor treatment by leveraging a synergistic effect. Hu et al. investigated the utilization of CAR-T cells in combination with immune checkpoint inhibitors in a murine model of melanoma. The biodegradable hydrogel encapsulates CAR-T cells and specifically targets human chondroitin sulfate proteoglycan 4 (CSPG4.CAR). The hydrogel is covered with nanoparticles that contain IL-15 and anti-PDL1. These nanoparticles are linked to human platelets. When anti-PDL1 and anti-IL-15 agents are administered together, the former can stimulate the development of CAR-T cells, and the latter can block the PD1/PDL1 pathway, allowing for the effective elimination of cancer cells [ 197 ]. Several efficient delivery methods have been developed for the administration and enhancement of CAR-T-cell accessibility to solid tumors. Surgically inaccessible or incompletely removed tumors can be precisely and efficiently targeted with biomedical polymeric devices developed through engineering. A complicated technique including the combination of soluble biomolecules with ligands for T-cell activation antibodies can be employed to achieve antitumor action against cancer cells. T lymphocyte migration to tumor sites was enhanced by three-dimensional bioscaffolds, such as polymerized alginate-collagen mimetic peptide matrices. This effect was also observed when porous silica microparticles were combined with the matrices, allowing for the encapsulation and controlled release of biomolecules over a prolonged period of time [ 198 ].

Personalized Immunotherapeutic Strategies Based on Unique Genetic and Molecular Tumor Profiles

Personalized cancer immunotherapy is an evolving frontier in oncology, enabling more effective, targeted, and safer treatment options on the basis of the molecular fingerprints of individual tumors. The following sections describe how such personalized strategies are tailored across major cancer types.

Melanoma: Neoantigen burden and TIL profiling

Melanoma is one of the most immunogenic cancers due to its high tumor mutational burden (TMB), which often results from ultraviolet radiation-induced DNA damage. This high mutational load creates numerous tumor-specific neoantigens that are easily recognized by cytotoxic T lymphocytes. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, are particularly effective in patients with elevated TMB and high PD-L1 expression. Additionally, the presence of TILs, especially CD8+ T cells, is a strong predictor of the immunotherapy response. Personalized vaccines based on tumor neoantigens and adoptive TIL therapies are also being developed. These therapies rely on sequencing the patient’s tumor and identifying dominant T-cell clones for ex vivo expansion and reinfusion, enabling a customized attack on tumor-specific targets [ 199 , 200 ].

Non-small cell lung cancer (NSCLC): TMB and STK11/KEAP1 mutation profiling

In NSCLC, personalized immunotherapy is guided by both mutational load and actionable genetic alterations. High TMB and MSI-H status are linked with better responses to PD-1/PD-L1 blockade. However, the presence of STK11 and KEAP1 mutations, which commonly cooccur with KRAS mutations, can negatively impact immune cell infiltration and responsiveness to immunotherapy. On the other hand, EGFR and ALK mutations often predict poor outcomes with ICIs, prompting the use of targeted therapies first. Molecular testing via next-generation sequencing (NGS) has become standard practice, helping clinicians decide whether to administer ICIs alone or in combination with chemotherapy or delay their use. Ongoing studies are also exploring gene expression-based immune signatures and the role of epigenetic modifiers in sensitizing NSCLC tumors to immunotherapy [ 201 , 202 ].

Colorectal Cancer (CRC): MSI-H/dMMR as a biomarker for PD-1 inhibitors

Colorectal cancer is one of the most well-established models of molecularly guided immunotherapy. Tumors that are microsatellite instability-high (MSI-H) or mismatch repair-deficiency (dMMR) exhibit high neoantigen loads and robust immune cell infiltration, making them ideal candidates for PD-1 inhibitors such as pembrolizumab. However, the majority of colorectal cancers are microsatellite stable (MSS) and immunologically "cold." Personalized strategies for these patients include combining ICIs with chemotherapy, anti-VEGF agents, or even gut microbiota modulation to improve immune responsiveness. Additionally, emerging evidence suggests that immune checkpoint efficacy can be enhanced through fecal microbiota transplantation or probiotic supplementation to restore microbial balance and immune activation in the tumor microenvironment [ 203 , 204 ].

Breast cancer: Subtype-specific immune strategies

Breast cancer is a heterogeneous disease, and the role of immunotherapy is most prominent in triple-negative breast cancer (TNBC). TNBC is often associated with increased mutational burden, increased PD-L1 expression, and increased presence of TILs, all of which are predictive markers for immunotherapy response. PD-L1 testing is routinely used to determine eligibility for therapies such as atezolizumab or pembrolizumab in TNBC patients. In contrast, hormone receptor-positive and HER2-positive subtypes are typically less immunogenic. However, molecular profiling of HER2+ cancers may reveal the eligibility of HER2-targeted CAR-T-cell therapies or bispecific antibodies. Additionally, BRCA1/2-mutated tumors may benefit from combined PARP inhibitors and immune checkpoint blockade, offering a personalized approach based on DNA repair deficiency [ 205 , 206 ].

Prostate Cancer: Low Immunogenicity and DNA Repair Defects

Prostate cancer has traditionally been considered immunologically “cold,” exhibiting a low TMB and minimal T-cell infiltration. However, a subset of patients with DNA damage repair (DDR) gene mutations—particularly mutations in BRCA1, BRCA2, and ATM—can benefit from PARP inhibitors and potentially from combination therapy with ICIs. Furthermore, the presence of AR-V7 splice variants in circulating tumor cells can influence the responsiveness to hormonal therapy versus immunotherapy. Sipuleucel-T, an autologous dendritic cell vaccine targeting prostatic acid phosphatase (PAP), exemplifies the personalization of immunotherapy in prostate cancer. Liquid biopsies are now being used to track androgen receptor mutations and other genomic changes, guiding personalized treatment plans in patients with metastatic castration-resistant prostate cancer (mCRPC) [ 207 ].

Glioblastoma: Personalized Neoantigen Vaccines and IDH Mutations

Glioblastoma (GBM) remains one of the most challenging cancers to treat with immunotherapy because of its immunosuppressive microenvironment and low TMB. However, molecular subtyping and mutation profiling offer opportunities for personalization. For example, tumors with IDH1 mutations may respond differently to immunotherapy than IDH1 wild-type tumors. Neoantigen-based peptide vaccines tailored to mutations such as EGFRvIII have shown early promise. Additionally, CAR-T cells targeting IL13Rα2 and HER2 are being explored in clinical trials, particularly when supported by tumor HLA typing and antigen expression profiles. Despite the ability of the blood‒brain barrier to limit immune cell access, novel delivery platforms and localized immunotherapy (e.g., intratumoral injections) are being developed to improve effectiveness in GBM patients [ 208 ].

Ovarian cancer: Immune subtypes and BRCA mutations

Ovarian cancer presents a moderate mutational burden but has subgroups that can benefit from personalized immunotherapy. BRCA1/2-mutated tumors show increased DNA damage signaling and may respond to PARP inhibitors in combination with ICIs. Tumors can also be categorized by immune gene signatures into immune-infiltrated or immune-desert subtypes, influencing the therapeutic response. HLA typing and neoantigen prediction have been used to design personalized dendritic cell vaccines and TCR-engineered T cells that target tumor antigens such as NY-ESO-1 or WT1. Additionally, the levels of cytokines, such as CXCL9 and CXCL10, and PD-L1 expression are being studied as biomarkers to stratify patients for immune-based therapies in advanced or platinum-resistant ovarian cancer [ 209 ].

Predictive Biomarkers for Stratifying Immunotherapy Responders

The identification of reliable predictive biomarkers is critical for optimizing patient selection, improving treatment efficacy, and minimizing unnecessary toxicity in cancer immunotherapy. Since immune checkpoint inhibitors and adoptive cell therapies do not benefit all patients equally, biomarkers help stratify those most likely to respond and guide personalized treatment strategies across various cancer types. One of the most widely studied biomarkers is PD-L1 expression on tumor and immune cells. High PD-L1 expression has been associated with improved response rates to anti-PD-1/PD-L1 agents in NSCLC, urothelial carcinoma, and triple-negative breast cancer. However, PD-L1 expression is heterogeneous, dynamic, and influenced by prior treatments, limiting its utility as a sole predictor [ 210 , 211 ]. TMB is another important biomarker reflecting the number of somatic mutations in a tumor. High TMB often correlates with increased neoantigen production, making tumors more recognizable to T cells [ 212 , 213 ]. Clinical trials, such as CheckMate 227, have shown that high TMB is associated with superior responses to nivolumab + ipilimumab in patients with NSCLC. TMB is also used as a tumor-agnostic biomarker for pembrolizumab in the FDA-approved indication for TMB ≥10 mutations/Mb [ 214 ]. The microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status serves as a robust predictive biomarker, especially in colorectal, endometrial, and gastric cancers. MSI-H tumors are immunologically "hot," often presenting with increased T-cell infiltration and neoantigen load. Pembrolizumab is FDA-approved for MSI-H/dMMR solid tumors, regardless of their tissue origin [ 215 ].

In addition to genomic markers, immune gene expression profiles, such as interferon-gamma (IFN-γ)-related signatures, have shown predictive value in patients with melanoma and renal cell carcinoma. Similarly, the density of TILs, especially CD8⁺ T cells at the invasive margin, is correlated with favorable immunotherapy responses in patients with melanoma and ovarian cancer [ 216 ]. Circulating biomarkers such as ctDNA dynamics, soluble PD-L1, and exosomal RNA offer minimally invasive methods to monitor therapy response and resistance in real time. For example, early decreases in ctDNA levels after immunotherapy initiation are associated with longer progression-free survival. HLA typing and T-cell receptor (TCR) repertoire diversity are also emerging tools for assessing the likelihood of successful antigen presentation and immune activation. Patients with diverse TCR clonotypes tend to mount stronger responses to checkpoint blockade [ 217 ]. Table 2 shows the predictive biomarkers for immunotherapy response for all types of cancer.

Finally, microbiome composition is being explored as a novel predictive biomarker, with studies showing that the presence of specific gut bacteria enhances the efficacy of PD-1 blockade, particularly in melanoma and colorectal cancer. Together, these biomarkers form the foundation for precision immuno-oncology, allowing clinicians to tailor treatment decisions, identify nonresponders early, and improve overall patient outcomes. Table 2 Predictive biomarkers for immunotherapy response across cancer types Biomarker Cancer Type(s) Predictive Role/Significance Associated Drugs/Immunotherapies PD-L1 expression NSCLC, TNBC, melanoma, bladder, gastric High PD-L1 correlates with improved response to PD-1/PD-L1 inhibitors Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab Tumor Mutational Burden (TMB) NSCLC, melanoma, bladder, cervical High TMB predicts better neoantigen load and ICI response Pembrolizumab (TMB ≥10 mutations/Mb), Nivolumab + Ipilimumab Microsatellite Instability-High (MSI-H)/dMMR Colorectal, endometrial, gastric, prostate Strong predictor of response due to high immunogenicity Pembrolizumab, Nivolumab TIL density (CD8+ T cells) Melanoma, ovarian, breast, cervical High TIL infiltration correlates with better ICI response General ICI predictor (not drug-specific) IFN-γ–related gene signature Melanoma, RCC Indicates a preinflamed TME conducive to ICI response Predictive of PD-1 blockade response Circulating tumor DNA (ctDNA) Lung, colorectal, breast, melanoma Early decline during treatment correlates with clinical response Dynamic response monitoring (nonspecific to drug) HLA typing & TCR clonality Melanoma, NSCLC Predicts antigen presentation and T-cell recognition TCR-T therapy, personalized vaccine selection Gut microbiota composition Melanoma, CRC, NSCLC Specific bacteria (e.g., Akkermansia , Bifidobacterium ) enhance ICI efficacy Modulates PD-1/PD-L1 responses; studied with FMT Beta-2 microglobulin (B2M) mutations Melanoma, prostate Associated with resistance to ICIs due to MHC-I loss Used in resistance prediction, not drug-targeted LAG-3 and TIM-3 expression Melanoma, HNSCC, gastric Emerging markers of immune exhaustion and ICI resistance Under investigation with dual checkpoint inhibitors

Combination Immunotherapy Strategies to Enhance Efficacy and Overcome Resistance

While immune checkpoint inhibitors and adoptive cell therapies have transformed cancer treatment, their effectiveness is limited in a significant proportion of patients due to primary or acquired resistance. Rational combination therapies have emerged as a potent strategy to overcome these barriers. By integrating immunotherapy with conventional and novel modalities, including chemotherapy, targeted therapy, radiotherapy, and microbiota modulation, researchers aim to increase tumor immunogenicity, improve immune cell infiltration, and sustain durable antitumor responses.

Immunotherapy Plus Chemotherapy

Chemotherapy can modulate the immune response by inducing ICD, increasing tumor antigen release, and reducing the number of immunosuppressive cells, such as regulatory T cells (Tregs) and MDSCs. Combining chemotherapy with immune checkpoint inhibitors has shown significant clinical benefit in several cancers. In NSCLC, the KEYNOTE-189 trial demonstrated that, compared with chemotherapy alone, combining pembrolizumab with platinum-based chemotherapy significantly improved overall survival [ 218 ]. Similarly, in TNBC, the IMpassion130 trial revealed that atezolizumab plus nab-paclitaxel improved progression-free survival (PFS) in PD-L1-positive patients [ 219 ]. In gastric cancer, the CheckMate 649 study evaluated nivolumab combined with oxaliplatin-based chemotherapy, which resulted in improved overall survival and a higher response rate in patients with a PD-L1 combined positive score (CPS ≥5). These results support the synergy between chemotherapy and immune checkpoint blockade across multiple solid tumors [ 220 ].

Immunotherapy Plus-Targeted Therapy

Targeted therapies against tumor-specific oncogenes (e.g., EGFR, BRAF, and VEGF) can alter the tumor microenvironment, enhancing immunogenicity and responsiveness to immunotherapy. One mechanism involves reducing VEGF-mediated immunosuppression and enhancing dendritic cell maturation. In renal cell carcinoma (RCC), the combination of avelumab (PD-L1 inhibitor) and axitinib (VEGFR inhibitor) led to superior PFS and OS compared with sunitinib monotherapy in the JAVELIN Renal 101 trial [ 221 ]. Another example is the CLEAR study, which reported that lenvatinib plus pembrolizumab extended PFS to 23.9 months compared with 9.2 months with sunitinib [ 222 ]. In melanoma, the COMBI-i trial investigated spartalizumab (PD-1) with dabrafenib and trametinib (BRAF/MEK inhibitors). Although not statistically significant overall, subgroup analysis suggested a benefit in certain molecular phenotypes with higher T-cell infiltration. Preclinical models also show that BRAF inhibitors increase antigen expression and immune infiltration, which can be exploited in personalized treatment plans [ 223 ]. In hepatocellular carcinoma, combining atezolizumab with bevacizumab (an anti-VEGF monoclonal antibody) was shown in the IMbrave150 trial to significantly improve OS and PFS over sorafenib monotherapy, reinforcing the concept that VEGF blockade can synergize with immune activation [ 224 ].

Immunotherapy plus radiotherapy

Radiation therapy not only causes tumor cell death but also enhances antigen presentation, increases MHC class I expression, and promotes the infiltration of immune cells into the tumor. These effects contribute to the abscopal effect, in which radiation at one site triggers immune-mediated regression at distant, unirradiated sites. A pivotal example is a phase II trial in metastatic NSCLC (the PEMBRO-RT study), where patients received pembrolizumab alone or after stereotactic body radiotherapy (SBRT) to a single lesion. The response rate nearly doubled in the radiotherapy plus pembrolizumab arm [ 225 ]. In melanoma, case reports and small trials have documented synergistic responses when combining anti-CTLA-4 (ipilimumab) with localized radiotherapy. Radiation acts as an in situ vaccine by releasing tumor antigens, enhancing systemic antitumor immunity. Ongoing trials are evaluating the optimal dosing, fractionation, and sequencing of radiotherapy with ICIs to optimize outcomes in patients with solid tumors such as head and neck cancer, prostate cancer, and glioblastoma [ 226 ].

Immunotherapy and Microbiota Modulation

The gut microbiome profoundly influences systemic immune responses and has emerged as a critical determinant of immunotherapy efficacy. Specific commensal bacteria have been linked to enhanced responses to checkpoint inhibitors, whereas dysbiosis often caused by antibiotic use is correlated with poor outcomes.

A landmark study by Routy et al. revealed that patients with NSCLC or RCC who had taken antibiotics had significantly reduced responses to PD-1 inhibitors. The presence of Akkermansia muciniphila and Faecalibacterium prausnitzii was associated with a restored ICI response in preclinical models [ 227 ]. In a phase I clinical trial, fecal microbiota transplantation (FMT) from ICI responders to ICI-resistant melanoma patients led to restored clinical responses in 30% of participants. Changes in microbial composition after FMT are correlated with increased T-cell activation and decreased MDSC populations [ 228 ]. Prebiotic and probiotic strategies are also being evaluated. In murine models, the administration of Bifidobacterium breve improved anti-PD-L1 efficacy through increased dendritic cell activation and CD8⁺ T-cell infiltration. Clinical trials are ongoing to assess the effects of dietary fiber, polyphenols, and live biotherapeutics in combination with immunotherapy [ 229 ].

Role of the Gut Microbiota in Enhancing Colorectal Cancer Immunotherapy

CRC, especially its MSS form, presents a major therapeutic challenge because of its poor response to immune checkpoint inhibitors (ICIs). Recent studies have revealed that the gut microbiota, which comprises trillions of commensal microorganisms, plays a pivotal role in regulating systemic immune responses and modulating tumor behavior. Modifying the microbiota has emerged as a promising strategy to increase the effectiveness of immunotherapy, especially when it is used in combination with other modalities, such as chemotherapy or immune checkpoint blockade [ 230 ].

Certain bacterial taxa, such as Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bifidobacterium longum, have been linked to improved antitumor immunity and better responses to ICIs in patients with CRC. These bacteria promote antigen presentation, enhance T-cell infiltration, and modulate cytokine profiles to favor an immunostimulatory TME [ 231 ]. For example, A. muciniphila enhances dendritic cell maturation and increases IL-12 production, thereby priming CD8+ cytotoxic T cells to recognize tumor antigens more effectively [ 232 ].

In a pivotal preclinical study, fecal microbiota transplantation (FMT) from ICI-responsive individuals into germ-free or antibiotic-treated mice with CRC significantly restored the response to anti-PD-1 therapy. These findings were translated into early-phase clinical trials. For example, a phase I trial demonstrated that combining FMT with nivolumab led to partial responses in immune-refractory metastatic melanoma patients, and similar trials are underway in MSS-CRC patients [ 233 ].

In addition to checkpoint blockade, chemotherapy and microbiota-targeted approaches show promise. Oxaliplatin and 5-FU can disrupt the intestinal barrier and microbiota composition, but when coadministered with microbiota-supportive agents (e.g., dietary fiber, prebiotics, or probiotic supplements), this negative impact may be reversed. These combinations enhance T-cell infiltration and reduce regulatory T cells in the tumor microenvironment [ 234 ]. Furthermore, novel synbiotics (prebiotic + probiotic combinations) and postbiotics (microbial metabolites such as butyrate or inosine) are under development to increase gut-immune signaling. Some of these agents can increase tumor MHC-I expression and T-cell priming, potentiating the efficacy of ICIs [ 235 ]. Overall, the integration of microbiota modulation into CRC treatment particularly for MSS tumors has immense potential to convert immunologically “cold” tumors into “hot,” therapy-responsive phenotypes. Future precision medicine approaches may involve personalized microbiome profiling, enabling the use of tailored microbial interventions alongside conventional or immunotherapy.

Emerging Combinations: Epigenetic and Metabolic Modulators

Novel agents targeting epigenetic regulators (e.g., HDAC inhibitors and DNA methyltransferase inhibitors) are being studied to reverse immune evasion. For example, entinostat, an HDAC inhibitor, increases MHC expression and the antigen processing machinery, sensitizing tumors to ICIs [ 236 ]. In ER-positive breast cancer, a phase II study of entinostat and atezolizumab demonstrated enhanced immune activation and preliminary clinical benefit. Similarly, metformin and IDO inhibitors are under investigation for their ability to reprogram tumor metabolism and overcome T-cell exhaustion [ 237 ]. Furthermore, nanoparticle-based platforms enable the codelivery of immunomodulatory drugs and ICIs for improved pharmacokinetics and safety profiles. A preclinical study using PLGA nanoparticles loaded with PD-L1 siRNA and an IL-2 plasmid revealed complete tumor regression in hepatocellular carcinoma models [ 238 ]. Table 3 shows a summary of combination immunotherapy strategies with clinical and preclinical evidence. Table 3 Summary of combination immunotherapy strategies with clinical and preclinical evidence Combination Strategy Cancer Type(s) Key Agents Study Example Outcome/Impact Immunotherapy + Chemotherapy NSCLC Pembrolizumab + platinum-based chemo KEYNOTE-189 (NEJM, 2018) Improved OS (22.0 vs. 10.7 months), higher response rates TNBC Atezolizumab + nab-paclitaxel IMpassion130 (NEJM, 2019) Longer PFS in PD-L1+ TNBC patients (7.5 vs. 5.0 months) Gastric cancer Nivolumab + oxaliplatin CheckMate 649 Improved OS in CPS ≥5 population Immunotherapy + Targeted Therapy RCC Avelumab + Axitinib JAVELIN Renal 101 Increased PFS (13.8 vs. 8.4 months) and OS RCC Lenvatinib + Pembrolizumab CLEAR Study PFS extended to 23.9 months Melanoma Spartalizumab + BRAF/MEK inhibitors COMBI-i Trial Improved T-cell infiltration (modest clinical benefit) HCC Atezolizumab + Bevacizumab IMbrave150 OS: 19.2 vs. 13.4 months compared to sorafenib Immunotherapy + Radiotherapy NSCLC Pembrolizumab + SBRT PEMBRO-RT Study Response rate doubled (41.7% vs. 19.2%) Melanoma Ipilimumab + Radiotherapy Case reports, early trials Observed abscopal effect in metastatic lesions Immunotherapy + Microbiota Modulation Melanoma, NSCLC PD-1 inhibitors + FMT Baruch et al., Restored ICI responsiveness in 30% of ICI-resistant patients NSCLC, RCC PD-1 inhibitors + commensal bacteria Routy et al., A. muciniphila improved ICI outcomes; antibiotics impaired response Immunotherapy + Epigenetic/Metabolic Modifiers Breast cancer Atezolizumab + Entinostat Phase II trial Increased MHC expression and TILs; early clinical benefit HCC (preclinical) PD-L1 siRNA + IL-2 plasmid (NP delivery) Liu et al., Complete tumor regression in mouse models

Strategies to Modify the Tumor Microenvironment to Overcome Immunosuppression

The tumor microenvironment (TME) plays a pivotal role in dictating the success or failure of immunotherapeutic interventions. In many solid tumors, the TME is highly immunosuppressive and characterized by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs, often M2-polarized), hypoxia, and inhibitory cytokines such as TGF-β and IL-10. These components collectively inhibit cytotoxic T-cell activity, impair antigen presentation, and facilitate immune escape. Thus, reprogramming the TME to a more immunostimulatory state is a critical goal in improving immunotherapy outcomes. One strategy involves targeting immunosuppressive cellular populations. Inhibitors of CSF1R have been used to deplete or repolarize M2 macrophages into proinflammatory M1 macrophages, enhancing antigen presentation and T-cell activation. Clinical trials using cabiralizumab (anti-CSF1R) in combination with PD-1 inhibitors have shown early signs of efficacy in treating pancreatic and lung cancers. Similarly, blockade of CCR4 (using mogamulizumab) has been used to deplete Tregs and improve immune responsiveness [ 239 , 240 ]. Similarly, blockade of CCR4 (using mogamulizumab) has been used to deplete Tregs and improve immune responsiveness [ 239 , 240 ].

Another approach is the use of IDO1 inhibitors, which block tryptophan metabolism, which contributes to immune suppression and T-cell anergy. Although early trials (e.g., epacadostat + pembrolizumab) failed to meet endpoints, next-generation indoleamine 2,3-dioxygenase (IDO) inhibitors and dual pathway inhibitors (e.g., IDO1/TDO2) are under investigation. Modulation of the tumor vasculature is another critical avenue. Anti-angiogenic agents such as bevacizumab normalize abnormal blood vessels, increase T-cell infiltration, and reduce hypoxia. When combined with immune checkpoint inhibitors—as demonstrated in hepatocellular carcinoma (IMbrave150 trial)—this approach improves TME accessibility and reduces immune evasion [ 241 ]. Targeting metabolic pathways is also gaining attention. Tumor cells often outcompete immune cells for glucose and amino acids. Agents such as arginase inhibitors, glutaminase inhibitors, and lactate dehydrogenase (LDH) blockers aim to restore the metabolic fitness of effector T cells within the TME [ 242 ]. Nanotechnology is increasingly being leveraged to deliver TME-modulating agents directly to the tumor site. For example, nanoparticles carrying TGF-β inhibitors, siRNAs, or IL-12 plasmids have shown success in reducing immune suppression and enhancing cytotoxic T-cell infiltration in preclinical models of breast and pancreatic cancer [ 243 ]. Finally, radiation and oncolytic viruses are used to transform immune "cold" tumors into "hot" tumors by promoting local inflammation and antigen release. These therapies also upregulate danger signals and chemokines (e.g., CXCL9/10), facilitating T-cell recruitment and activation [ 244 ]. Together, these strategies aim to shift the TME from an immunosuppressive milieu to one that favors immune recognition and tumor elimination, ultimately improving the efficacy and durability of immunotherapeutic responses.

Clinical Trials and Patents in Immunotherapy for Cancer Treatment

Immunotherapy, which uses the immune system of the body to fight tumors, is one of the most exciting new ways to treat cancer. Clinical trials form the backbone of evaluating the safety and efficacy of these innovative therapies across various cancer types, aiming to translate scientific discoveries into viable treatments. Concurrently, patents play a crucial role in protecting intellectual property related to novel immunotherapeutic agents and delivery technologies, fostering innovation and investment in this rapidly evolving field. Tables 4 , 5 outline current clinical trials exploring diverse immunotherapeutic approaches and highlight key patents that underscore ongoing advancements in cancer immunotherapy. Table 4 Clinical Trials and Patients in Immunotherapy for Cancer Treatment Delivery Technology Therapy Cancer Type Clinical Trial Identifier Reference Intravenous Infusion Nivolumab (Opdivo) + Ipilimumab (Yervoy) Non-Small Cell Lung Cancer (NSCLC) NCT02477826 [ 245 ] Intratumoral Injection Talimogene laherparepvec (T-VEC) Melanoma NCT02263508 [ 246 ] Oral Administration Axalimogene filolisbac (ADXS-HPV) Cervical Cancer NCT01266460 [ 247 ] CAR T-Cell Therapy Axicabtagene ciloleucel (Yescarta) Diffuse Large B-Cell Lymphoma NCT02348216 [ 248 ] mRNA Vaccine mRNA-4157 Solid Tumors NCT03313778 [ 249 ] Oncolytic Virus CG0070 Bladder Cancer NCT02365818 [ 250 ] Bite Antibody Blinatumomab (Blincyto) Acute Lymphoblastic Leukemia NCT02013167 [ 251 ] Peptide Vaccine PVX-410 Multiple Myeloma NCT01718899 [ 252 ] Nanoparticle Delivery nanocamptothecin CRLX101 with capecitabine Various Solid Tumors NCT02010567 [ 253 ] Radiolabeled Antibody Ibritumomab tiuxetan (Zevalin) Non-Hodgkin's Lymphoma NCT00514908 [ 254 ] Table 5 Patents Related to Cancer Immunotherapy Patent Number Title Assignee Summary US10072132B2 Anti-PD-1 Antibody Merck Sharp & Dohme Corp. This patent describes to pembrolizumab (Keytruda), which is an anti-PD-1 monoclonal antibody employed in the treatment of several types of cancer. US9821057B2 Anti-CTLA-4 Antibodies and Their Uses Bristol-Myers Squibb Company This patent involves ipilimumab (Yervoy), an anti-CTLA-4 antibody utilized in melanoma treatment. US10300138B2 Compositions and Methods for Enhancing Anti-Tumor Immunity Genentech, Inc. Focuses on combination therapies involving checkpoint inhibitors and costimulatory molecules. RU2017102769A CAR T Cells Specific for EGFRvIII and Uses Thereof Juno Therapeutics, Inc. For glioblastoma, this patent talks about CAR-T cells that target EGFRvIII. US7235641B2 Bispecific Antibodies for T-Cell Activation Amgen Inc. Covers bispecific T-cell engager (BiTE) antibodies that simultaneously target tumor cells and T cells. AU2017210031B2 NK Cell Therapies Fate Therapeutics, Inc. Involves methods for producing and using natural killer (NK) cells for immunotherapeutic applications. US20090010948A1 Anti-tumor vaccines delivered by dendritic cells devoid of interleukin-10 Fang Ping Huang, Yu Xiao Chen, Kwan Man This patent describes anti-tumor vaccines delivered by dendritic cells that do not produce interleukin-10, which is an immunosuppressive cytokine. US20040156846A1 Therapy via targeted delivery of nanoscale particles using L6 antibodies Wolfgang Daum, Gerald DeNardo, Diane Ellis-Busby, Alan Foreman, Douglas Gwost, Erik Handy, Robert Ivkov Covers targeted delivery of nanoscale particles to cancer cells using L6 antibodies. WO2017151727A1 Enhanced cancer immunotherapy by microneedle patch-assisted delivery Zhen GU, Chao Wang, Yanqi YE Describes the use of microneedle patches to enhance the delivery of cancer immunotherapy agents. US20160361268A1 Intralymphatic delivery of hyaluronan nanoparticle for cancer metastasis Chih-Peng Liu, Ya-Chin Lo, Ming-Cheng Wei, Maggie LU, Shuen-Hsiang CHOU, Shih-Ta Chen, Hsiang-Wen TSENG Discusses the use of hyaluronan nanoparticles for intralymphatic delivery to prevent cancer metastasis. WO2011097384A2 Tumor targeted delivery of immunomodulators by nanoplymers Dapeng Zhou, Li Chun, Patrick Hwu Focuses on tumor-targeted delivery of immunomodulatory agents using nanopolymers. US8785371B2 Drug delivery of temozolomide for systemic based treatment of cancer Rameshwar Patil, Eggehard Holler, Keith L. Black, Julia Y. Ljubimova This patent describes a method for the systemic delivery of temozolomide for treating cancer. US20160346204A1 Nanoscale carriers for the delivery or codelivery of chemotherapeutics, nucleic acids, and photosensitizers Wenbin Lin, Chunbai He, Demin Liu Covers the use of nanoscale carriers for delivering chemotherapeutics, nucleic acids, and photosensitizers. US9610250B2 Nanolipogel vehicles for controlled delivery of different pharmaceutical agents Tarek M. Fahmy, Eric STERN, Richard A. Flavell, Jason Park, Alyssa Siefert, Stephen H. Wrzesinski Discusses nanolipogel vehicles for the controlled delivery of various pharmaceutical agents. US20080044484A1 Use of polymeric nanoparticles for vaccine delivery Boris Minev Describes the use of polymeric nanoparticles to deliver vaccines. US20040038406A1 Nanoparticle delivery systems and methods of use thereof Gretchen Unger, Beverly Lundell Covers various nanoparticle delivery systems and their methods of use.

Challenges and Limitations of Cancer Immunotherapy

Cancer immunotherapy has revolutionized cancer treatment by providing new hope in areas where conventional medicines have failed. However, several challenges and limitations still impede its widespread success, as shown in Table 4 . One major challenge is the heterogeneity of tumors. Cancer is not a singular disease but a collection of disorders with diverse genetic and molecular profiles, complicating the development of universal immunotherapeutic strategies [ 255 ]. Additionally, the tumor microenvironment (TME) often has immunosuppressive characteristics that hinder the efficacy of immunotherapies. Elements within the TME, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and certain cytokines, can inhibit the activity of effector immune cells, reducing overall treatment effectiveness [ 256 , 257 ].

The frequency of immune-related adverse events (irAEs) is another major problem. Even though immunotherapies such as checkpoint inhibitors are very new, they can cause serious autoimmune reactions because they cause the immune system to attack healthy tissues. These irAEs range from mild skin rashes to severe, life-threatening conditions affecting various organs, necessitating careful management and sometimes the discontinuation of therapy [ 258 ]. Furthermore, the development of resistance to immunotherapy poses a substantial hurdle. Some patients initially respond well to treatments but eventually develop resistance, leading to disease progression. This resistance can be intrinsic, where tumors do not respond from the outset, or acquired, where tumors initially respond but later relapse. The mechanisms underlying resistance are complex and include genetic mutations, alterations in antigen presentation, and adaptive immune resistance mechanisms [ 259 , 260 ].

The cost and accessibility of immunotherapies are also significant concerns. These treatments are often expensive, limiting their availability to a broader population, especially in low- and middle-income countries. The complex manufacturing processes and the need for highly specialized administration further exacerbate these issues, creating disparities in treatment access [ 261 , 262 ]. Therefore, while cancer immunotherapy holds tremendous promise, addressing the challenges of tumor heterogeneity, the immunosuppressive tumor microenvironment, immune-related adverse events, resistance mechanisms, and cost barriers are crucial for its future success and broader applicability.

Conclusion and Future Perspectives

Cancer immunotherapy has become a revolutionary method for treating cancer, increasing patient survival rates and quality of life. The advent of immune checkpoint inhibitors, CAR-T-cell therapies, cancer vaccines, cytokine therapies, and oncolytic viruses has significantly broadened the therapeutic arsenal against various malignancies. Recent advances in delivery modalities have further enhanced the precision and efficacy of these therapies, allowing for more targeted and personalized treatment strategies. However, the journey of cancer immunotherapy is fraught with challenges. Issues such as immune-related adverse events, high costs, and variable patient responses underscore the need for a deeper understanding of the underlying mechanisms and the development of predictive biomarkers. Additionally, the complexity of the TME and the potential for immune escape mechanisms necessitate innovative approaches to overcome these hurdles.

Future research should focus on elucidating the molecular and cellular interactions within the tumor microenvironment, developing combination therapies to increase treatment efficacy and reduce resistance, and identifying novel biomarkers for better patient stratification. Advances in bioinformatics and systems biology will be crucial in unraveling the complexities of immune responses and tailoring treatments to individual patient profiles. Moreover, expanding the accessibility and affordability of cancer immunotherapies remains a critical goal. Collaborative efforts among academia, industry, and regulatory bodies are essential to streamline the development and approval processes, ensuring that these life-saving treatments reach a broader patient population.

In conclusion, while significant strides have been made in the field of cancer immunotherapy, the journey is far from over. By addressing the existing challenges and exploring new avenues, we can pave the way for more effective, safe, and accessible immunotherapies. The future of cancer treatment lies in the continued innovation and integration of immunotherapy into comprehensive cancer care, ultimately bringing us closer to a world where cancer is a manageable and curable disease.

Abbreviations

Antigen-Presenting Cells

Chimeric Antigen Receptor T-cell

Cytotoxic T-lymphocyte antigen 4

Food and Drug Administration

Human papillomavirus

Interleukin

Programmed death-1

Programmed death-ligand 1

Quality by Design

T lymphocytes

X-radiation

Hepatitis C Virus

Prostatic acid phosphatase

Granulocyte-Macrophage Colony-Stimulating Factor

Interferons

Natural killer (cells)

Interleukin-2

Interferon-alpha

Herpes simplex viruses

Enhanced permeability and retention

Epithelial cell adhesion molecule

Human liver cancer cell line

Myeloid-derived suppressor cells

Immunogenic cell death

Major histocompatibility complexes

Cytotoxic T lymphocytes

Extracellular vesicles

Tumor-infiltrating lymphocytes

Polymer-Nanoparticle

Chondroitin sulfate proteoglycan 4 chimeric antigen receptor

Metal-Organic Frameworks

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Authors' contributions

M.D contributed toward validation, resources, and project administration; B.C.V contributed toward investigation and formal analysis.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

References

1. Brown JS Amend SR Austin RH Gatenby RA Hammarlund EU Pienta KJ Updating the definition of cancer Mol Cancer Res 2023 10.1158/1541-7786.MCR-23-0411 37409952 PMC10618731 Brown JS, Amend SR, Austin RH, Gatenby RA, Hammarlund EU, Pienta KJ. Updating the Definition of Cancer. Molecular Cancer Research. 2023;2110.1158/1541-7786.MCR-23-0411 37409952 10.1158/1541-7786.MCR-23-0411 PMC10618731

2. Can G. Cancer basics. Medical Nursing. 2023.

3. Debela DT Muzazu SGY Heraro KD Ndalama MT Mesele BW Haile DC New approaches and procedures for cancer treatment: current perspectives SAGE Open Med 2021 10.1177/20503121211034366 34408877 PMC8366192 Debela DT, Muzazu SGY, Heraro KD, Ndalama MT, Mesele BW, Haile DC, et al. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med. 2021.10.1177/20503121211034366 34408877 10.1177/20503121211034366 PMC8366192

4. McCune JS Immunotherapy to treat cancer Clin Pharmacol Ther 2016 10.1002/cpt.404 27513619 McCune JS. Immunotherapy to Treat Cancer. Clin Pharmacol Ther. 2016.10.1002/cpt.404 27513619 10.1002/cpt.404

5. McCune JS Rapid advances in immunotherapy to treat cancer Clin Pharmacol Ther 2018 10.1002/cpt.985 29527663 McCune JS. Rapid Advances in Immunotherapy to Treat Cancer. Clin Pharmacol Ther. 2018.10.1002/cpt.985 29527663 10.1002/cpt.985

6. Boardman DA Levings MK Cancer immunotherapies repurposed for use in autoimmunity Nat Biomed Eng 2019 10.1038/s41551-019-0359-6 30952977 Boardman DA, Levings MK. Cancer immunotherapies repurposed for use in autoimmunity. Nat Biomed Eng. 2019.10.1038/s41551-019-0359-6 30952977 10.1038/s41551-019-0359-6

7. American Cancer Society. How immunotherapy is used to treat cancer. American Cancer Society. 2019;

8. Amin M Lockhart AC The potential role of immunotherapy to treat colorectal cancer Expert Opin Investig Drugs 2015 10.1517/13543784.2015.985376 25519074 Amin M, Lockhart AC. The potential role of immunotherapy to treat colorectal cancer. Expert Opin Investig Drugs. 2015.10.1517/13543784.2015.985376 25519074 10.1517/13543784.2015.985376

9. Gupta SL Basu S Soni V Jaiswal RK Immunotherapy: an alternative promising therapeutic approach against cancers Mol Biol Rep 2022 10.1007/s11033-022-07525-8 35759082 PMC9244230 Gupta SL, Basu S, Soni V, Jaiswal RK. Immunotherapy: an alternative promising therapeutic approach against cancers. Mol Biol Rep. 2022.10.1007/s11033-022-07525-8 35759082 10.1007/s11033-022-07525-8 PMC9244230

10. Taefehshokr N Baradaran B Baghbanzadeh A Taefehshokr S Promising approaches in cancer immunotherapy Immunobiology 2020 10.1016/j.imbio.2019.11.010 31812343 Taefehshokr N, Baradaran B, Baghbanzadeh A, Taefehshokr S. Promising approaches in cancer immunotherapy. Immunobiology. 2020. 10.1016/j.imbio.2019.11.010 31812343 10.1016/j.imbio.2019.11.010

11. Shiravand Y Khodadadi F Kashani SMA Hosseini-Fard SR Hosseini S Sadeghirad H Immune checkpoint inhibitors in cancer therapy Curr Oncol 2022 10.3390/curroncol29050247 35621637 PMC9139602 Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, et al. Immune Checkpoint Inhibitors in Cancer Therapy. Current Oncology. 2022.10.3390/curroncol29050247 35621637 10.3390/curroncol29050247 PMC9139602

12. Robert C A decade of immune-checkpoint inhibitors in cancer therapy Nat Commun 2020 10.1038/s41467-020-17670-y 32732879 PMC7393098 Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020.10.1038/s41467-020-17670-y 32732879 10.1038/s41467-020-17670-y PMC7393098

13. Basudan AM. The role of immune checkpoint inhibitors in cancer therapy. Clin Pract. 2023. 10.3390/clinpract13010003 PMC9844484 36648843

14. Uscanga-Palomeque AC Chávez-Escamilla AK Alvizo-Báez CA Saavedra-Alonso S Terrazas-Armendáriz LD Tamez-Guerra RS CAR-T-cell therapy: from the shop to cancer therapy Int J Mol Sci 2023 10.3390/ijms242115688 37958672 PMC10649325 Uscanga-Palomeque AC, Chávez-Escamilla AK, Alvizo-Báez CA, Saavedra-Alonso S, Terrazas-Armendáriz LD, Tamez-Guerra RS, et al. CAR-T-Cell Therapy: From the Shop to Cancer Therapy. Int J Mol Sci. 2023.10.3390/ijms242115688 37958672 10.3390/ijms242115688 PMC10649325

15. Kaczmarek M Poznańska J Fechner F Michalska N Paszkowska S Napierała A Cancer vaccine therapeutics: limitations and effectiveness—a literature review Cells 2023 10.3390/cells12172159 37681891 PMC10486481 Kaczmarek M, Poznańska J, Fechner F, Michalska N, Paszkowska S, Napierała A, et al. Cancer Vaccine Therapeutics: Limitations and Effectiveness—A Literature Review. Cells. 2023. 10.3390/cells12172159 37681891 10.3390/cells12172159 PMC10486481

16. Qiu Y Su M Liu L Tang Y Pan Y Sun J Clinical application of cytokines in cancer immunotherapy Drug Des Devel Ther 2021 10.2147/DDDT.S308578 34079226 PMC8166316 Qiu Y, Su M, Liu L, Tang Y, Pan Y, Sun J. Clinical application of cytokines in cancer immunotherapy. Drug Des Devel Ther. 2021.10.2147/DDDT.S308578 34079226 10.2147/DDDT.S308578 PMC8166316

17. Lee S Margolin K Cytokines in cancer immunotherapy Cancers (Basel) 2011 10.3390/cancers3043856 24213115 PMC3763400 Lee S, Margolin K. Cytokines in cancer immunotherapy. Cancers (Basel). 2011.10.3390/cancers3043856 24213115 10.3390/cancers3043856 PMC3763400

18. Lugowska I, Teterycz P, Rutkowski P. Immunotherapy of melanoma. Wspolczesna Onkologia. 2017;2. 10.5114/wo.2018.73889 PMC5885078 29628796

19. Redman JM Gibney GT Atkins MB Advances in immunotherapy for melanoma BMC Med 2016 10.1186/s12916-016-0571-0 26850630 PMC4744430 Redman JM, Gibney GT, Atkins MB. Advances in immunotherapy for melanoma. BMC Med. 2016.10.1186/s12916-016-0571-0 26850630 10.1186/s12916-016-0571-0 PMC4744430

20. Xabier Mielgo-Rubio EAULQCMSM. Immunotherapy in non-small cell lung cancer: update and new insights. J Clin Transl Res. 2021. PMC8177026 34104805

21. Salzer E Attarbaschi A The value of immunotherapy in pediatric leukemia and lymphoma memo 2021 10.1007/s12254-021-00764-8 Salzer E, Attarbaschi A. The value of immunotherapy in pediatric leukemia and lymphoma. Memo - Magazine of European Medical Oncology. 2021.10.1007/s12254-021-00764-8

22. Scotté F, Ratta R, Beuzeboc P. Side effects of immunotherapy. Curr Opin Oncol. 2019;31. 10.1097/CCO.0000000000000541 30925538

23. Hronek J. Research is needed to better understand combination immunotherapy side effects. ONS Voice. 2020;35.

24. Leana Huntley TE. Understanding immunotherapy side effects. NCCN Guidlelines for Patients. 2020;

25. Arumugam P Manicka Vasagam J Jayaseelan VP NKAP: a new m6A RNA binding protein predicts prognosis and immunotherapy response in head and neck squamous cell carcinoma J Stomatol Oral Maxillofac Surg 2025 10.1016/j.jormas.2025.102265 39870194 Arumugam P, Manicka Vasagam J, Jayaseelan VP. NKAP: A new m6A RNA binding protein predicts prognosis and immunotherapy response in head and neck squamous cell carcinoma. J Stomatol Oral Maxillofac Surg [Internet]. 2025;126.10.1016/j.jormas.2025.102265 39870194 10.1016/j.jormas.2025.102265

26. Fritah H Rovelli R Chiang CLL Kandalaft LE The current clinical landscape of personalized cancer vaccines Cancer Treat Rev 2022 10.1016/j.ctrv.2022.102383 35367804 Fritah H, Rovelli R, Chiang CLL, Kandalaft LE. The current clinical landscape of personalized cancer vaccines. Cancer Treat Rev. 2022.10.1016/j.ctrv.2022.102383 35367804 10.1016/j.ctrv.2022.102383

27. Marhelava K Pilch Z Bajor M Graczyk-Jarzynka A Zagozdzon R Targeting negative and positive immune checkpoints with monoclonal antibodies in therapy of cancer Cancers (Basel) 2019 10.3390/cancers11111756 31717326 PMC6895894 Marhelava K, Pilch Z, Bajor M, Graczyk-Jarzynka A, Zagozdzon R. Targeting negative and positive immune checkpoints with monoclonal antibodies in therapy of cancer. Cancers (Basel). 2019.10.3390/cancers11111756 31717326 10.3390/cancers11111756 PMC6895894

28. Sharma P Allison JP Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential Cell 2015 10.1016/j.cell.2015.03.030 25860605 PMC5905674 Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential. Cell. 2015.10.1016/j.cell.2015.03.030 25860605 10.1016/j.cell.2015.03.030 PMC5905674

29. Kim SK Cho SW The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment Front Pharmacol 2022 10.3389/fphar.2022.868695 35685630 PMC9171538 Kim SK, Cho SW. The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment. Front Pharmacol. 2022.10.3389/fphar.2022.868695 35685630 10.3389/fphar.2022.868695 PMC9171538

30. Waldman AD Fritz JM Lenardo MJ A guide to cancer immunotherapy: from T-cell basic science to clinical practice Nat Rev Immunol 2020 10.1038/s41577-020-0306-5 32433532 PMC7238960 Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T-cell basic science to clinical practice. Nat Rev Immunol. 2020. 10.1038/s41577-020-0306-5 32433532 10.1038/s41577-020-0306-5 PMC7238960

31. Gardner D Jeffery LE Sansom DM Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade Am J Transplant 2014 10.1111/ajt.12834 25098238 Gardner D, Jeffery LE, Sansom DM. Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade. American Journal of Transplantation. 2014.10.1111/ajt.12834 25098238 10.1111/ajt.12834

32. Lipson EJ Drake CG Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma Clin Cancer Res 2011 10.1158/1078-0432.CCR-11-1595 21900389 PMC3575079 Lipson EJ, Drake CG. Ipilimumab: An anti-CTLA-4 antibody for metastatic melanoma. Clinical Cancer Research. 2011.10.1158/1078-0432.CCR-11-1595 21900389 10.1158/1078-0432.CCR-11-1595 PMC3575079

33. Gao J Shi LZ Zhao H Chen J Xiong L He Q Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy Cell 2016 10.1016/j.cell.2016.08.069 27667683 PMC5088716 Lipson EJ, Drake CG. Ipilimumab: An anti-CTLA-4 antibody for metastatic melanoma. Clinical Cancer Research. 2011. 10.1016/j.cell.2016.08.069 21900389 10.1158/1078-0432.CCR-11-1595 PMC3575079

34. Du Rusquec P Saint-Jean M Brocard A Peuvrel L Khammari A Quéreux G Ipilimumab-induced autoimmune pancytopenia in a case of metastatic melanoma J Immunother 2014 10.1097/CJI.0000000000000041 24911795 Du Rusquec P, Saint-Jean M, Brocard A, Peuvrel L, Khammari A, Quéreux G, et al. Ipilimumab-induced autoimmune pancytopenia in a case of metastatic melanoma. Journal of Immunotherapy. 2014;37.10.1097/CJI.0000000000000041 24911795 10.1097/CJI.0000000000000041

35. Keir ME Butte MJ Freeman GJ Sharpe AH PD-1 and its ligands in tolerance and immunity Annu Rev Immunol 2008 10.1146/annurev.immunol.26.021607.090331 18173375 PMC10637733 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008.10.1146/annurev.immunol.26.021607.090331 18173375 10.1146/annurev.immunol.26.021607.090331 PMC10637733

36. Patsoukis N Wang Q Strauss L Boussiotis VA Revisiting the PD-1 pathway Sci Adv 2020 10.1126/sciadv.abd2712 32948597 PMC7500922 Patsoukis N, Wang Q, Strauss L, Boussiotis VA. Revisiting the PD-1 pathway. Sci Adv. 2020;6.10.1126/sciadv.abd2712 32948597 10.1126/sciadv.abd2712 PMC7500922

37. Philips EA Liu J Kvalvaag A Mørch AM Tocheva AS Ng C Transmembrane domain–driven PD-1 dimers mediate T-cell inhibition Sci Immunol 2024 10.1126/sciimmunol.ade6256 38457513 PMC11166110 Philips EA, Liu J, Kvalvaag A, Mørch AM, Tocheva AS, Ng C, et al. Transmembrane domain–driven PD-1 dimers mediate T-cell inhibition. Sci Immunol. 2024;9.10.1126/sciimmunol.ade6256 38457513 10.1126/sciimmunol.ade6256 PMC11166110

38. Dang TO, Ogunniyi A, Barbee MS, Drilon A. Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Expert Rev Anticancer Ther. 2016;16. 10.1586/14737140.2016.1123626 PMC4993158 26588948

39. Brahmer JR, Lee JS, Ciuleanu TE, Bernabe Caro R, Nishio M, Urban L, et al. Five-year survival outcomes with Nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small cell lung cancer in CheckMate 227. Journal of Clinical Oncology. 2023;41. 10.1200/JCO.22.01503 PMC9937094 36223558

40. Hellmann MD Paz-Ares L Bernabe Caro R Zurawski B Kim S-W Carcereny Costa E Nivolumab plus ipilimumab in advanced non–small-cell lung cancer N Engl J Med 2019 10.1056/NEJMoa1910231 31562796 Philips EA, Liu J, Kvalvaag A, Mørch AM, Tocheva AS, Ng C, et al. Transmembrane domain–driven PD-1 dimers mediate T-cell inhibition. Sci Immunol. 2024;9. 10.1056/NEJMoa1910231 38457513 10.1126/sciimmunol.ade6256 PMC11166110

41. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019. 10.1186/s12943-019-1091-2 PMC6833286 31690319

42. Das M Zhu C Kuchroo VK Tim-3 and its role in regulating anti-tumor immunity Immunol Rev 2017 10.1111/imr.12520 28258697 PMC5512889 Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017.10.1111/imr.12520 28258697 10.1111/imr.12520 PMC5512889

43. Kandel S Adhikary P Li G Cheng K The TIM3/Gal9 signaling pathway: an emerging target for cancer immunotherapy Cancer Lett 2021 10.1016/j.canlet.2021.04.011 33895262 PMC8168453 Kandel S, Adhikary P, Li G, Cheng K. The TIM3/Gal9 signaling pathway: An emerging target for cancer immunotherapy. Cancer Lett. 2021. 10.1016/j.canlet.2021.04.011 33895262 10.1016/j.canlet.2021.04.011 PMC8168453

44. Sauer N Janicka N Szlasa W Skinderowicz B Kołodzińska K Dwernicka W TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors Cancer Immunol Immunother 2023 10.1007/s00262-023-03516-1 37567938 PMC10576709 Sauer N, Janicka N, Szlasa W, Skinderowicz B, Kołodzińska K, Dwernicka W, et al. TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors. Cancer Immunology, Immunotherapy. 2023. 10.1007/s00262-023-03516-1 37567938 10.1007/s00262-023-03516-1 PMC10576709

45. Seliger B Combinatorial approaches with checkpoint inhibitors to enhance anti-tumor immunity Front Immunol 2019 10.3389/fimmu.2019.00999 31178856 PMC6538766 Seliger B. Combinatorial Approaches with Checkpoint Inhibitors to Enhance Anti-tumor Immunity. Front Immunol. 2019.10.3389/fimmu.2019.00999 31178856 10.3389/fimmu.2019.00999 PMC6538766

46. Huo JL Wang YT Fu WJ Lu N Liu ZS The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application Front Immunol 2022 10.3389/fimmu.2022.956090 35958563 PMC9361790 Huo JL, Wang YT, Fu WJ, Lu N, Liu ZS. The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application. Front Immunol. 2022.10.3389/fimmu.2022.956090 35958563 10.3389/fimmu.2022.956090 PMC9361790

47. Chocarro L Blanco E Zuazo M Arasanz H Bocanegra A Fernández-Rubio L Understanding lag-3 signaling Int J Mol Sci 2021 10.3390/ijms22105282 34067904 PMC8156499 Chocarro L, Blanco E, Zuazo M, Arasanz H, Bocanegra A, Fernández-Rubio L, et al. Understanding lag-3 signaling. Int J Mol Sci. 2021.10.3390/ijms22105282 34067904 10.3390/ijms22105282 PMC8156499

48. Aggarwal V Workman CJ Vignali DAA LAG-3 as the third checkpoint inhibitor Nat Immunol 2023 10.1038/s41590-023-01569-z 37488429 PMC11144386 Aggarwal V, Workman CJ, Vignali DAA. LAG-3 as the third checkpoint inhibitor. Nat Immunol. 2023;24.10.1038/s41590-023-01569-z 37488429 10.1038/s41590-023-01569-z PMC11144386

49. Gestermann N Saugy D Martignier C Tillé L Fuertes Marraco SA Zettl M LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T-cell cocultures Oncoimmunology 2020 10.1080/2162402X.2020.1736792 32850194 PMC7422827 Gestermann N, Saugy D, Martignier C, Tillé L, Fuertes Marraco SA, Zettl M, et al. LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T-cell cocultures. Oncoimmunology. 2020;9. 10.1080/2162402X.2020.1736792 32850194 10.1080/2162402X.2020.1736792 PMC7422827

50. Long L Zhang X Chen F Pan Q Phiphatwatchara P Zeng Y The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy Genes Cancer 2018 10.18632/genesandcancer.180 30603054 PMC6305110 Long L, Zhang X, Chen F, Pan Q, Phiphatwatchara P, Zeng Y, et al. The promising immune checkpoint LAG-3: From tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9.10.18632/genesandcancer.180 30603054 10.18632/genesandcancer.180 PMC6305110

51. Sauer N Szlasa W Jonderko L Oślizło M Kunachowicz D Kulbacka J LAG-3 as a potent target for novel anticancer therapies of a wide range of tumors Int J Mol Sci 2022 10.3390/ijms23179958 36077354 PMC9456311 Sauer N, Szlasa W, Jonderko L, Oślizło M, Kunachowicz D, Kulbacka J, et al. LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors. Int J Mol Sci. 2022.10.3390/ijms23179958 36077354 10.3390/ijms23179958 PMC9456311

52. Maruhashi T Sugiura D Okazaki IM Okazaki T LAG-3: from molecular functions to clinical applications J Immunother Cancer 2020 10.1136/jitc-2020-001014 32929051 PMC7488795 Sauer N, Szlasa W, Jonderko L, Oślizło M, Kunachowicz D, Kulbacka J, et al. LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors. Int J Mol Sci. 2022. 10.1136/jitc-2020-001014 36077354 10.3390/ijms23179958 PMC9456311

53. Tang W Chen J Ji T Cong X TIGIT, a novel immune checkpoint therapy for melanoma Cell Death Dis 2023 10.1038/s41419-023-05961-3 37495610 PMC10372028 Tang W, Chen J, Ji T, Cong X. TIGIT, a novel immune checkpoint therapy for melanoma. Cell Death Dis. 2023.10.1038/s41419-023-05961-3 37495610 10.1038/s41419-023-05961-3 PMC10372028

54. Yeo J Ko M Lee DH Park Y Jin HS Tigit/cd226 axis regulates anti-tumor immunity Pharmaceuticals 2021 10.3390/ph14030200 33670993 PMC7997242 Yeo J, Ko M, Lee DH, Park Y, Jin HS. Tigit/cd226 axis regulates anti-tumor immunity. Pharmaceuticals. 2021. 10.3390/ph14030200 33670993 10.3390/ph14030200 PMC7997242

55. Rotte A, Sahasranaman S, Budha N. Targeting tigit for immunotherapy of cancer: Update on clinical development. Biomedicines. 2021;9. 10.3390/biomedicines9091277 PMC8472042 34572463

56. Chu X Tian W Wang Z Zhang J Zhou R Coinhibition of TIGIT and PD-1/PD-L1 in cancer immunotherapy: mechanisms and clinical trials Mol Cancer 2023 10.1186/s12943-023-01800-3 37291608 PMC10249258 Chu X, Tian W, Wang Z, Zhang J, Zhou R. Coinhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials. Mol Cancer. 2023.10.1186/s12943-023-01800-3 37370104 10.1186/s12943-023-01812-z PMC10294354

57. National Cancer Institute. CAR T cells: engineering patients’ immune cells to treat their cancers. National Cancer Institute. 2022.

58. Bhat AA Altamimi ASA Goyal A Goyal K Kaur I Kumar S The role of CD95 in modulating CAR T-cell therapy: challenges and therapeutic opportunities in oncology Int Immunopharmacol 2025 10.1016/j.intimp.2024.113675 39608172 Bhat AA, Altamimi ASA, Goyal A, Goyal K, Kaur I, Kumar S, et al. The role of CD95 in modulating CAR T-cell therapy: Challenges and therapeutic opportunities in oncology. Int Immunopharmacol [Internet]. 2025;144.10.1016/j.intimp.2024.113675 39608172 10.1016/j.intimp.2024.113675

59. Almohaimeed HM Chowdhury A Sarkar S Almars AI Tounsi WA Singh A Advances in cancer immunotherapy: the role of super NK and super CAR-T cells Int Immunopharmacol 2025 10.1016/j.intimp.2025.115074 40513329 Almohaimeed HM, Chowdhury A, Sarkar S, Almars AI, Tounsi WA, Singh A, et al. Advances in cancer immunotherapy: The role of super NK and super CAR-T cells. Int Immunopharmacol [Internet]. 2025;161.10.1016/j.intimp.2025.115074 40513329 10.1016/j.intimp.2025.115074

60. Globerson Levin A Rivière I Eshhar Z Sadelain M CAR T cells: building on the CD19 paradigm Eur J Immunol 2021 10.1002/eji.202049064 34196410 PMC9392049 Globerson Levin A, Rivière I, Eshhar Z, Sadelain M. CAR T cells: Building on the CD19 paradigm. Eur J Immunol. 2021.10.1002/eji.202049064 34196410 10.1002/eji.202049064 PMC9392049

61. Zhang Y Zhou W Yang J Yang J Wang W Chimeric antigen receptor engineered natural killer cells for cancer therapy Exp Hematol Oncol 2023 10.1186/s40164-023-00431-0 37563648 PMC10413722 Zhang Y, Zhou W, Yang J, Yang J, Wang W. Chimeric antigen receptor engineered natural killer cells for cancer therapy. Exp Hematol Oncol. 2023.10.1186/s40164-023-00431-0 37563648 10.1186/s40164-023-00431-0 PMC10413722

62. Alhabbab RY Targeting cancer stem cells by genetically engineered chimeric antigen receptor T cells Front Genet 2020 10.3389/fgene.2020.00312 32391048 PMC7188929 Alhabbab RY. Targeting Cancer Stem Cells by Genetically Engineered Chimeric Antigen Receptor T Cells. Front Genet. 2020. 10.3389/fgene.2020.00312 32391048 10.3389/fgene.2020.00312 PMC7188929

63. Chen T Deng J Zhang Y Liu B Liu R Zhu Y The construction of modular universal chimeric antigen receptor T (MU-CAR-T) cells by covalent linkage of allogeneic T cells and various antibody fragments Mol Cancer 2024 10.1186/s12943-024-01938-8 38468291 PMC10926606 Chen T, Deng J, Zhang Y, Liu B, Liu R, Zhu Y, et al. The construction of modular universal chimeric antigen receptor T (MU-CAR-T) cells by covalent linkage of allogeneic T cells and various antibody fragments. Mol Cancer. 2024;23. 10.1186/s12943-024-01938-8 38468291 10.1186/s12943-024-01938-8 PMC10926606

64. Duan Z, Lin Z, Zhou S. Universal CAR T cell: engineering of universal T cell, modular CAR system, and applications. 2021.

65. Sterner RC Sterner RM CAR-T-cell therapy: current limitations and potential strategies Blood Cancer J 2021 10.1038/s41408-021-00459-7 33824268 PMC8024391 Sterner RC, Sterner RM. CAR-T-cell therapy: current limitations and potential strategies. Blood Cancer J. 2021.10.1038/s41408-021-00459-7 33824268 10.1038/s41408-021-00459-7 PMC8024391

66. Smirnov S Mateikovich P Samochernykh K Shlyakhto E Recent advances on CAR-T signaling pave the way for prolonged persistence and new modalities in clinic Front Immunol 2024 10.3389/fimmu.2024.1335424 38455066 PMC10918004 Smirnov S, Mateikovich P, Samochernykh K, Shlyakhto E. Recent advances on CAR-T signaling pave the way for prolonged persistence and new modalities in clinic. Front Immunol. 2024.10.3389/fimmu.2024.1335424 38455066 10.3389/fimmu.2024.1335424 PMC10918004

67. Benmebarek MR Karches CH Cadilha BL Lesch S Endres S Kobold S Killing mechanisms of chimeric antigen receptor (CAR) T cells Int J Mol Sci 2019 10.3390/ijms20061283 30875739 PMC6470706 Benmebarek MR, Karches CH, Cadilha BL, Lesch S, Endres S, Kobold S. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019.10.3390/ijms20061283 30875739 10.3390/ijms20061283 PMC6470706

68. Hong M Clubb JD Chen YY Engineering CAR-T cells for next-generation cancer therapy Cancer Cell 2020 10.1016/j.ccell.2020.07.005 32735779 Hong M, Clubb JD, Chen YY. Engineering CAR-T Cells for Next-Generation Cancer Therapy. Cancer Cell. 2020.10.1016/j.ccell.2020.07.005 32735779 10.1016/j.ccell.2020.07.005

69. Smith AJ Oertle J Warren D Prato D Chimeric antigen receptor (CAR) T-cell therapy for malignant cancers: summary and perspective J Cell Immunother 2016 10.1016/j.jocit.2016.08.001 Smith AJ, Oertle J, Warren D, Prato D. Chimeric antigen receptor (CAR) T-cell therapy for malignant cancers: Summary and perspective. Journal of Cellular Immunotherapy. 2016;2.10.1016/j.jocit.2016.08.001

70. Acuto O, Michel F. CD28-mediated costimulation: a quantitative support for TCR signaling. Nat Rev Immunol. 2003. 10.1038/nri1248 14647476

71. Hombach A Wieczarkowiecz A Marquardt T Heuser C Usai L Pohl C Tumor-specific T-cell activation by recombinant immunoreceptors: CD3ζ signaling and CD28 costimulation are simultaneously, required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3ζ signaling receptor molecule J Immunol 2001 10.4049/jimmunol.167.11.6123 11714771 Hombach A, Wieczarkowiecz A, Marquardt T, Heuser C, Usai L, Pohl C, et al. Tumor-Specific T-Cell Activation by Recombinant Immunoreceptors: CD3ζ Signaling and CD28 Costimulation Are Simultaneously, Required for Efficient IL-2 Secretion and Can Be Integrated Into One Combined CD28/CD3ζ Signaling Receptor Molecule. The Journal of Immunology. 2001;167. 10.4049/jimmunol.167.11.6123 11714771 10.4049/jimmunol.167.11.6123

72. Kagoya Y Tanaka S Guo T Anczurowski M Wang CH Saso K A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects Nat Med 2018 10.1038/nm.4478 29400710 PMC5839992 Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, Saso K, et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med. 2018;24. 10.1038/nm.4478 29400710 10.1038/nm.4478 PMC5839992

73. Finney HM Lawson ADG Bebbington CR Weir ANC Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product J Immunol 1998 10.4049/jimmunol.161.6.2791 9743337 Finney HM, Lawson ADG, Bebbington CR, Weir ANC. Chimeric Receptors Providing Both Primary and Costimulatory Signaling in T Cells from a Single Gene Product. The Journal of Immunology. 1998;161.10.4049/jimmunol.161.6.2791 9743337

74. Tokarew N Ogonek J Endres S von Bergwelt-Baildon M Kobold S Teaching an old dog new tricks: next-generation CAR T cells Br J Cancer 2019 10.1038/s41416-018-0325-1 30413825 PMC6325111 Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, Kobold S. Teaching an old dog new tricks: next-generation CAR T cells. Br J Cancer. 2019.10.1038/s41416-018-0325-1 30413825 10.1038/s41416-018-0325-1 PMC6325111

75. Du S, Yan J, Xue Y, Zhong Y, Dong Y. Adoptive cell therapy for cancer treatment. Exploration. 2023;3. 10.1002/EXP.20210058 PMC10624386 37933232

76. Fesnak AD June CH Levine BL Engineered T cells: the promise and challenges of cancer immunotherapy Nat Rev Cancer 2016 10.1038/nrc.2016.97 27550819 PMC5543811 Fesnak AD, June CH, Levine BL. Engineered T cells: The promise and challenges of cancer immunotherapy. Nat Rev Cancer. 2016. 10.1038/nrc.2016.97 27550819 10.1038/nrc.2016.97 PMC5543811

77. Rapoport AP Stadtmauer EA Binder-Scholl GK Goloubeva O Vogl DT Lacey SF NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma Nat Med 2015 10.1038/nm.3910 26193344 PMC4529359 Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21. 10.1038/nm.3910 26193344 10.1038/nm.3910 PMC4529359

78. Kershaw MH Westwood JA Darcy PK Gene-engineered T cells for cancer therapy Nat Rev Cancer 2013 10.1038/nrc3565 23880905 Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013.10.1038/nrc3565 23880905 10.1038/nrc3565

79. Zhang J Wang L The emerging world of TCR-T-cell trials against cancer: a systematic review Technol Cancer Res Treat 2019 10.1177/1533033819831068 30798772 PMC6391541 Zhang J, Wang L. The emerging world of TCR-T-cell trials against cancer: A systematic review. Technol Cancer Res Treat. 2019. 10.1177/1533033819831068 30798772 10.1177/1533033819831068 PMC6391541

80. Liu S Galat V Galat Y Lee YKA Wainwright D Wu J NK cell-based cancer immunotherapy: from basic biology to clinical development J Hematol Oncol 2021 10.1186/s13045-020-01014-w 33407739 PMC7788999 Liu S, Galat V, Galat4 Y, Lee YKA, Wainwright D, Wu J. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol. 202110.1186/s13045-020-01014-w 33407739 10.1186/s13045-020-01014-w PMC7788999

81. Kennedy LB Salama AKS A review of cancer immunotherapy toxicity CA Cancer J Clin 2020 10.3322/caac.21596 31944278 Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70.10.3322/caac.21596 31944278 10.3322/caac.21596

82. Liu E Marin D Banerjee P Macapinlac HA Thompson P Basar R Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors N Engl J Med 2020 10.1056/NEJMoa1910607 32023374 PMC7101242 Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. New England Journal of Medicine. 2020;382. 10.1056/NEJMoa1910607 32023374 10.1056/NEJMoa1910607 PMC7101242

83. Casanova-Acebes M Dalla E Leader AM LeBerichel J Nikolic J Morales BM Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells Nature 2021 10.1038/s41586-021-03651-8 34135508 PMC8923521 Casanova-Acebes M, Dalla E, Leader AM, LeBerichel J, Nikolic J, Morales BM, et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature. 2021;595.10.1038/s41586-021-03651-8 34135508 10.1038/s41586-021-03651-8 PMC8923521

84. Moradinasab S Pourbagheri-Sigaroodi A Ghaffari SH Bashash D Targeting macrophage-mediated tumor cell phagocytosis: an overview of phagocytosis checkpoints blockade, nanomedicine intervention, and engineered CAR-macrophage therapy Int Immunopharmacol 2022 10.1016/j.intimp.2021.108499 34972068 Moradinasab S, Pourbagheri-Sigaroodi A, Ghaffari SH, Bashash D. Targeting macrophage-mediated tumor cell phagocytosis: An overview of phagocytosis checkpoints blockade, nanomedicine intervention, and engineered CAR-macrophage therapy. Int Immunopharmacol. 2022.10.1016/j.intimp.2021.108499 34972068 10.1016/j.intimp.2021.108499

85. Morrissey MA Williamson AP Steinbach AM Roberts EW Kern N Headley MB Chimeric antigen receptors that trigger phagocytosis Elife 2018 10.7554/eLife.36688 29862966 PMC6008046 Morrissey MA, Williamson AP, Steinbach AM, Roberts EW, Kern N, Headley MB, et al. Chimeric antigen receptors that trigger phagocytosis. Elife. 2018;7. 10.7554/eLife.36688 29862966 10.7554/eLife.36688 PMC6008046

86. Liu J, Fu M, Wang M, Wan D, Wei Y, Wei X. Cancer vaccines as promising immuno-therapeutics: platforms and current progress. J Hematol Oncol. 2022. 10.1186/s13045-022-01247-x PMC8931585 35303904

87. Grimmett E, Al-Share B, Alkassab MB, Zhou RW, Desai A, Rahim MMA, et al. Cancer vaccines: past, present and future; a review article. Discover Oncology. 2022. 10.1007/s12672-022-00491-4 PMC9108694 35576080

88. Schiller JT, Davies P. Delivering on the promise: HPV vaccines and cervical cancer. Nat Rev Microbiol. 2004;2. 10.1038/nrmicro867 15031733

89. Kamolratanakul S Pitisuttithum P Human papillomavirus vaccine efficacy and effectiveness against cancer Vaccines 2021 10.3390/vaccines9121413 34960159 PMC8706722 Morrissey MA, Williamson AP, Steinbach AM, Roberts EW, Kern N, Headley MB, et al. Chimeric antigen receptors that trigger phagocytosis. Elife. 2018;7.10.3390/vaccines9121413 29862966 10.7554/eLife.36688 PMC6008046

90. Rizzo GEM Cabibbo G Craxì A Hepatitis B virus-associated hepatocellular carcinoma Viruses 2022 10.3390/v14050986 35632728 PMC9146458 Rizzo GEM, Cabibbo G, Craxì A. Hepatitis B Virus-Associated Hepatocellular Carcinoma. Viruses. 2022.10.3390/v14050986 35632728 10.3390/v14050986 PMC9146458

91. Ghanaat M Goradel NH Arashkia A Ebrahimi N Ghorghanlu S Malekshahi ZV Virus against virus: strategies for using adenovirus vectors in the treatment of HPV-induced cervical cancer Acta Pharmacol Sin 2021 10.1038/s41401-021-00616-5 33633364 PMC8633276 Ghanaat M, Goradel NH, Arashkia A, Ebrahimi N, Ghorghanlu S, Malekshahi ZV, et al. Virus against virus: strategies for using adenovirus vectors in the treatment of HPV-induced cervical cancer. Acta Pharmacol Sin. 2021. 10.1038/s41401-021-00616-5 33633364 10.1038/s41401-021-00616-5 PMC8633276

92. Fan T, Zhang M, Yang J, Zhu Z, Cao W, Dong C. Therapeutic cancer vaccines: advancements, challenges, and prospects. Signal Transduct Target Ther. 2023. 10.1038/s41392-023-01674-3 PMC10716479 38086815

93. Kurilin V Alshevskaya A Sennikov S Development of cell technologies based on dendritic cells for immunotherapy of oncological diseases Biomedicines 2024 10.3390/biomedicines12030699 38540312 PMC10968364 Kurilin V, Alshevskaya A, Sennikov S. Development of Cell Technologies Based on Dendritic Cells for Immunotherapy of Oncological Diseases. Biomedicines. 2024.10.3390/biomedicines12030699 38540312 10.3390/biomedicines12030699 PMC10968364

94. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T Immunotherapy for castration-resistant prostate cancer. New England Journal of Medicine. 2010;363. 10.1056/NEJMoa1001294 20818862

95. Cheever MA Higano CS Provenge (sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine Clin Cancer Res 2011 10.1158/1078-0432.CCR-10-3126 21471425 Cheever MA, Higano CS. PROVENGE (sipuleucel-T) in prostate cancer: The first FDA-approved therapeutic cancer vaccine. Clinical Cancer Research. 2011.10.1158/1078-0432.CCR-10-3126 21471425 10.1158/1078-0432.CCR-10-3126

96. Abd-Aziz N Poh CL Development of peptide-based vaccines for cancer J Oncol 2022 10.1155/2022/9749363 35342400 PMC8941562 Abd-Aziz N, Poh CL. Development of Peptide-Based Vaccines for Cancer. J Oncol. 2022.10.1155/2022/9749363 35342400 10.1155/2022/9749363 PMC8941562

97. Bubenik J. Dendritic cell-based cancer vaccines. Folia Biol (Praha). 1999. 10730892

98. Palucka K Banchereau J Dendritic-cell-based therapeutic cancer vaccines Immunity 2013 10.1016/j.immuni.2013.07.004 23890062 PMC3788678 Palucka K, Banchereau J. Dendritic-Cell-Based Therapeutic Cancer Vaccines. Immunity. 2013.10.1016/j.immuni.2013.07.004 23890062 10.1016/j.immuni.2013.07.004 PMC3788678

99. Miao L Zhang Y Huang L mRNA vaccine for cancer immunotherapy Mol Cancer 2021 10.1186/s12943-021-01335-5 33632261 PMC7905014 Miao L, Zhang Y, Huang L. mRNA vaccine for cancer immunotherapy. Mol Cancer. 2021.10.1186/s12943-021-01335-5 33632261 10.1186/s12943-021-01335-5 PMC7905014

100. Duan LJ Wang Q Zhang C Yang DX Zhang XY Potentialities and challenges of mRNA vaccine in cancer immunotherapy Front Immunol 2022 10.3389/fimmu.2022.923647 35711457 PMC9196868 Duan LJ, Wang Q, Zhang C, Yang DX, Zhang XY. Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy. Front Immunol. 2022.10.3389/fimmu.2022.923647 35711457 10.3389/fimmu.2022.923647 PMC9196868

101. Deng Z, Tian Y, Song J, An G, Yang P. mRNA vaccines: the dawn of a new era of cancer immunotherapy. Front Immunol. 2022. 10.3389/fimmu.2022.887125 PMC9201022 35720301

102. Hu Q Wu M Fang C Cheng C Zhao M Fang W Engineering nanoparticle-coated bacteria as oral DNA vaccines for cancer immunotherapy Nano Lett 2015 10.1021/acs.nanolett.5b00570 25806599 Hu Q, Wu M, Fang C, Cheng C, Zhao M, Fang W, et al. Engineering Nanoparticle-Coated Bacteria as Oral DNA Vaccines for Cancer Immunotherapy. Nano Lett. 2015;15. 10.1021/acs.nanolett.5b00570 25806599 10.1021/acs.nanolett.5b00570

103. Yang B Jeang J Yang A Wu TC Hung CF DNA vaccine for cancer immunotherapy Hum Vaccin Immunother 2014 10.4161/21645515.2014.980686 25625927 PMC4514137 Yang B, Jeang J, Yang A, Wu TC, Hung CF. DNA vaccine for cancer immunotherapy. Hum Vaccin Immunother. 2014;10. 10.4161/21645515.2014.980686 25625927 10.4161/21645515.2014.980686 PMC4514137

104. Conlon KC Miljkovic MD Waldmann TA Cytokines in the treatment of cancer J Interferon Cytokine Res 2019 10.1089/jir.2018.0019 29889594 PMC6350412 Conlon KC, Miljkovic MD, Waldmann TA. Cytokines in the Treatment of Cancer. Journal of Interferon and Cytokine Research. 2019;39. 10.1089/jir.2018.0019 29889594 10.1089/jir.2018.0019 PMC6350412

105. Atallah-Yunes SA Robertson MJ Cytokine based immunotherapy for cancer and lymphoma: biology, challenges and future perspectives Front Immunol 2022 10.3389/fimmu.2022.872010 35529882 PMC9067561 Atallah-Yunes SA, Robertson MJ. Cytokine Based Immunotherapy for Cancer and Lymphoma: Biology, Challenges and Future Perspectives. Front Immunol. 2022. 10.3389/fimmu.2022.872010 35529882 10.3389/fimmu.2022.872010 PMC9067561

106. Jiang T Zhou C Ren S Role of IL-2 in cancer immunotherapy Oncoimmunology 2016 10.1080/2162402x.2016.1163462 27471638 PMC4938354 Atallah-Yunes SA, Robertson MJ. Cytokine Based Immunotherapy for Cancer and Lymphoma: Biology, Challenges and Future Perspectives. Front Immunol. 2022.10.1080/2162402x.2016.1163462 35529882 10.3389/fimmu.2022.872010 PMC9067561

107. Choudhry H Helmi N Abdulaal WH Zeyadi M Zamzami MA Wu W Prospects of IL-2 in cancer immunotherapy BioMed Res Int 2018 10.1155/2018/9056173 29854806 PMC5960517 Choudhry H, Helmi N, Abdulaal WH, Zeyadi M, Zamzami MA, Wu W, et al. Prospects of IL-2 in Cancer Immunotherapy. Biomed Res Int. 2018. 10.1155/2018/9056173 29854806 10.1155/2018/9056173 PMC5960517

108. Kirkwood J Cancer immunotherapy: the interferon-α experience Semin Oncol 2002 10.1053/sonc.2002.33078 12068384 Kirkwood J. Cancer immunotherapy: The interferon-α experience. Semin Oncol. 2002;29.10.1053/sonc.2002.33078 12068384 10.1053/sonc.2002.33078

109. Aricò E, Castiello L, Capone I, Gabriele L, Belardelli F. Type i interferons and cancer: An evolving story demanding novel clinical applications. Cancers (Basel). 2019;11. 10.3390/cancers11121943 PMC6966569 31817234

110. Lee HM Lee HJ Chang JE Inflammatory cytokine: an attractive target for cancer treatment Biomedicines 2022 10.3390/biomedicines10092116 36140220 PMC9495935 Lee HM, Lee HJ, Chang JE. Inflammatory Cytokine: An Attractive Target for Cancer Treatment. Biomedicines. 2022.10.3390/biomedicines10092116 36140220 10.3390/biomedicines10092116 PMC9495935

111. Chiocca EA Rabkin SD Oncolytic viruses and their application to cancer immunotherapy Cancer Immunol Res 2014 10.1158/2326-6066.CIR-14-0015 24764576 PMC4303349 Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2.10.1158/2326-6066.CIR-14-0015 24764576 10.1158/2326-6066.CIR-14-0015 PMC4303349

112. Ylösmäki E Cerullo V Design and application of oncolytic viruses for cancer immunotherapy Curr Opin Biotechnol 2020 10.1016/j.copbio.2019.11.016 31874424 Ylösmäki E, Cerullo V. Design and application of oncolytic viruses for cancer immunotherapy. Curr Opin Biotechnol. 2020.10.1016/j.copbio.2019.11.016 31874424 10.1016/j.copbio.2019.11.016

113. Omole RK Oluwatola O Akere MT Eniafe J Agboluaje EO Daramola OB Comprehensive assessment on the applications of oncolytic viruses for cancer immunotherapy Front Pharmacol 2022 10.3389/fphar.2022.1082797 36569326 PMC9772532 Omole RK, Oluwatola O, Akere MT, Eniafe J, Agboluaje EO, Daramola OB, et al. Comprehensive assessment on the applications of oncolytic viruses for cancer immunotherapy. Front Pharmacol. 2022. 10.3389/fphar.2022.1082797 36569326 10.3389/fphar.2022.1082797 PMC9772532

114. Tang C Li L Mo T Na J Qian Z Fan D Oncolytic viral vectors in the era of diversified cancer therapy: from preclinical to clinical Clin Transl Oncol 2022 10.1007/s12094-022-02830-x 35612653 PMC9131313 Tang C, Li L, Mo T, Na J, Qian Z, Fan D, et al. Oncolytic viral vectors in the era of diversified cancer therapy: from preclinical to clinical. Clinical and Translational Oncology. 2022.10.1007/s12094-022-02830-x 35612653 10.1007/s12094-022-02830-x PMC9131313

115. Malogolovkin A Gasanov N Egorov A Weener M Ivanov R Karabelsky A Combinatorial approaches for cancer treatment using oncolytic viruses: projecting the perspectives through clinical trials outcomes Viruses 2021 10.3390/v13071271 34209981 PMC8309967 Malogolovkin A, Gasanov N, Egorov A, Weener M, Ivanov R, Karabelsky A. Combinatorial approaches for cancer treatment using oncolytic viruses: Projecting the perspectives through clinical trials outcomes. Viruses. 2021. 10.3390/v13071271 34209981 10.3390/v13071271 PMC8309967

116. Zolaly MA, Mahallawi W, Khawaji ZY, Alahmadi MA. The clinical advances of oncolytic viruses in cancer immunotherapy. Cureus. 2023; 10.7759/cureus.40742 PMC10361339 37485097

117. Kaufman HL Kohlhapp FJ Zloza A Oncolytic viruses: a new class of immunotherapy drugs Nat Rev Drug Discov 2015 10.1038/nrd4663 26323545 PMC7097180 Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: A new class of immunotherapy drugs. Nat Rev Drug Discov. 2015.10.1038/nrd4663 26323545 10.1038/nrd4663 PMC7097180

118. Huang S van Duijnhoven SMJ Sijts AJAM van Elsas A Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy J Cancer Res Clin Oncol 2020 10.1007/s00432-020-03404-6 32989604 PMC7679314 Huang S, van Duijnhoven SMJ, Sijts AJAM, van Elsas A. Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J Cancer Res Clin Oncol. 2020.10.1007/s00432-020-03404-6 32989604 10.1007/s00432-020-03404-6 PMC7679314

119. Blanco B Domínguez-Alonso C Alvarez-Vallina L Bispecific immunomodulatory antibodies for cancer immunotherapy Clin Cancer Res 2021 10.1158/1078-0432.CCR-20-3770 34108185 PMC9306338 Blanco B, Domínguez-Alonso C, Alvarez-Vallina L. Bispecific Immunomodulatory Antibodies for Cancer Immunotherapy. Clinical Cancer Research. 2021.10.1158/1078-0432.CCR-20-3770 34108185 10.1158/1078-0432.CCR-20-3770 PMC9306338

120. Zhang T, Lin Y, Gao Q. Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy. Cancer Biol Med. 2023. 10.20892/j.issn.2095-3941.2023.0002 PMC10038071 36971124

121. Goebeler ME Bargou R Blinatumomab: A CD19/CD3 bispecific T-cell engager (BiTE) with unique anti-tumor efficacy Leuk Lymphoma 2016 10.3109/10428194.2016.1161185 27050240 Goebeler ME, Bargou R. Blinatumomab: A CD19/CD3 bispecific T-cell engager (BiTE) with unique anti-tumor efficacy. Leuk Lymphoma. 2016;57.10.3109/10428194.2016.1161185 27050240 10.3109/10428194.2016.1161185

122. Zhao L Li S Wei X Qi X Liu D Liu L A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL Blood 2022 10.1182/blood.2022016243 35981465 Zhao L, Li S, Wei X, Qi X, Liu D, Liu L, et al. A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL. Blood. 2022;140. 10.1182/blood.2022016243 35981465 10.1182/blood.2022016243

123. Ma J, Mo Y, Tang M, Shen J, Qi Y, Zhao W, et al. Bispecific antibodies: from research to clinical application. Front Immunol. 2021. 10.3389/fimmu.2021.626616 PMC8131538 34025638

124. Guo X Wu Y Xue Y Xie N Shen G Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment Front Immunol 2023 10.3389/fimmu.2023.1291836 38106416 PMC10722299 Guo X, Wu Y, Xue Y, Xie N, Shen G. Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment. Front Immunol. 2023. 10.3389/fimmu.2023.1291836 38106416 10.3389/fimmu.2023.1291836 PMC10722299

125. Choi YH Song HS Lee SK Song CH Kim JH Han KH Advancements in bispecific antibody development and research trends Microbiol Biotechnol Lett 2023 10.48022/mbl.2307.07014 Choi YH, Song HS, Lee SK, Song CH, Kim JH, Han KH. Advancements in Bispecific Antibody Development and Research Trends. Microbiology and Biotechnology Letters. 2023.10.48022/mbl.2307.07014

126. Muthukutty P Woo HY Ragothaman M Yoo SY Recent advances in cancer immunotherapy delivery modalities Pharmaceutics 2023 10.3390/pharmaceutics15020504 36839825 PMC9967630 Muthukutty P, Woo HY, Ragothaman M, Yoo SY. Recent Advances in Cancer Immunotherapy Delivery Modalities. Pharmaceutics. 2023.10.3390/pharmaceutics15020504 36839825 10.3390/pharmaceutics15020504 PMC9967630

127. Roth A Rohrbach F Weth R Frisch B Schuber F Wels WS Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct Br J Cancer 2005 10.1038/sj.bjc.6602526 15812545 PMC2362007 Roth A, Rohrbach F, Weth R, Frisch B, Schuber F, Wels WS. Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct. Br J Cancer. 2005;92.10.1038/sj.bjc.6602526 15812545 10.1038/sj.bjc.6602526 PMC2362007

128. Yuba E, Harada A, Sakanishi Y, Watarai S, Kono K. A liposome-based antigen delivery system using pH-sensitive fusogenic polymers for cancer immunotherapy. Biomaterials. 2013;34. 10.1016/j.biomaterials.2012.12.031 23374704

129. Zheng Y Stephan MT Gai SA Abraham W Shearer A Irvine DJ In vivo targeting of adoptively transferred T cells with antibody- and cytokine-conjugated liposomes J Control Release 2013 10.1016/j.jconrel.2013.05.037 23770010 PMC4046900 Zheng Y, Stephan MT, Gai SA, Abraham W, Shearer A, Irvine DJ. In vivo targeting of adoptively transferred T cells with antibody- and cytokine-conjugated liposomes. Journal of Controlled Release. 2013;172.10.1016/j.jconrel.2013.05.037 23770010 10.1016/j.jconrel.2013.05.037 PMC4046900

130. Aoyama K Kuroda S Morihiro T Kanaya N Kubota T Kakiuchi Y Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system Sci Rep 2017 10.1038/s41598-017-14717-x 29074882 PMC5658411 Aoyama K, Kuroda S, Morihiro T, Kanaya N, Kubota T, Kakiuchi Y, et al. Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system. Sci Rep. 2017;7.10.1038/s41598-017-14717-x 29074882 10.1038/s41598-017-14717-x PMC5658411

131. Liu J Liu X Han Y Zhang J Liu D Ma G Nanovaccine incorporated with hydroxychloroquine enhances antigen cross-presentation and promotes antitumor immune responses ACS Appl Mater Interfaces 2018 10.1021/acsami.8b09348 30136844 Liu J, Liu X, Han Y, Zhang J, Liu D, Ma G, et al. Nanovaccine Incorporated with Hydroxychloroquine Enhances Antigen Cross-Presentation and Promotes Antitumor Immune Responses. ACS Appl Mater Interfaces. 2018;10.10.1021/acsami.8b09348 30136844 10.1021/acsami.8b09348

132. Reda M Ngamcherdtrakul W Nelson MA Siriwon N Wang R Zaidan HY Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment Nat Commun 2022 10.1038/s41467-022-31926-9 35871223 PMC9308817 Reda M, Ngamcherdtrakul W, Nelson MA, Siriwon N, Wang R, Zaidan HY, et al. Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment. Nat Commun. 2022;13.10.1038/s41467-022-31926-9 35871223 10.1038/s41467-022-31926-9 PMC9308817

133. Yu Y, Li J, Song B, Ma Z, Zhang Y, Sun H, et al. Polymeric PD-L1 blockade nanoparticles for cancer photothermal-immunotherapy. Biomaterials. 2022;280. 10.1016/j.biomaterials.2021.121312 34896861

134. Huang KW Hsu FF Qiu JT Chern GJ Lee YA Chang CC Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer Sci Adv 2020 10.1126/sciadv.aax5032 31998834 PMC6962042 Huang KW, Hsu FF, Qiu JT, Chern GJ, Lee YA, Chang CC, et al. Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer. Sci Adv. 2020;6.10.1126/sciadv.aax5032 31998834 10.1126/sciadv.aax5032 PMC6962042

135. Roy DG Bell JC Bourgeois-Daigneault MC Magnetic targeting of oncolytic VSV-based therapies improves infection of tumor cells in the presence of virus-specific neutralizing antibodies in vitro Biochem Biophys Res Commun 2020 10.1016/j.bbrc.2020.03.135 32248971 Roy DG, Bell JC, Bourgeois-Daigneault MC. Magnetic targeting of oncolytic VSV-based therapies improves infection of tumor cells in the presence of virus-specific neutralizing antibodies in vitro. Biochem Biophys Res Commun. 2020;526.10.1016/j.bbrc.2020.03.135 32248971 10.1016/j.bbrc.2020.03.135

136. Tresilwised N Pithayanukul P Mykhaylyk O Holm PS Holzmüller R Anton M Boosting oncolytic adenovirus potency with magnetic nanoparticles and magnetic force Mol Pharm 2010 10.1021/mp100123t 20550160 Tresilwised N, Pithayanukul P, Mykhaylyk O, Holm PS, Holzmüller R, Anton M, et al. Boosting oncolytic adenovirus potency with magnetic nanoparticles and magnetic force. Mol Pharm. 2010;7.10.1021/mp100123t 20550160 10.1021/mp100123t

137. Yin Y Li X Ma H Zhang J Yu D Zhao R In situ transforming RNA nanovaccines from polyethylenimine functionalized graphene oxide hydrogel for durable cancer immunotherapy Nano Lett 2021 10.1021/acs.nanolett.0c05039 33594887 Yin Y, Li X, Ma H, Zhang J, Yu D, Zhao R, et al. In Situ Transforming RNA Nanovaccines from Polyethylenimine Functionalized Graphene Oxide Hydrogel for Durable Cancer Immunotherapy. Nano Lett. 2021;21.10.1021/acs.nanolett.0c05039 33594887 10.1021/acs.nanolett.0c05039

138. Wang C Sun W Wright G Wang AZ Gu Z Inflammation-triggered cancer immunotherapy by programmed delivery of CpG and anti-PD1 antibody Adv Mater 2016 10.1002/adma.201506312 27558441 PMC5283805 Wang C, Sun W, Wright G, Wang AZ, Gu Z. Inflammation-Triggered Cancer Immunotherapy by Programmed Delivery of CpG and Anti-PD1 Antibody. Advanced Materials. 2016;28. 10.1002/adma.201506312 27558441 10.1002/adma.201506312 PMC5283805

139. Liu S Jiang Q Zhao X Zhao R Wang Y Wang Y A DNA nanodevice-based vaccine for cancer immunotherapy Nat Mater 2021 10.1038/s41563-020-0793-6 32895504 Liu S, Jiang Q, Zhao X, Zhao R, Wang Y, Wang Y, et al. A DNA nanodevice-based vaccine for cancer immunotherapy. Nat Mater. 2021;20.10.1038/s41563-020-0793-6 32895504 10.1038/s41563-020-0793-6

140. Ni Q, Zhang F, Liu Y, Wang Z, Yu G, Liang B, et al. A biadjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer. Sci Adv. 2020;6. 10.1126/sciadv.aaw6071 PMC7080439 32206706

141. Zhang Y Shen T Zhou S Wang W Lin S Zhu G Ph-responsive STING-activating DNA nanovaccines for cancer immunotherapy Adv Ther 2020 10.1002/adtp.202000083 34337143 PMC8323737 Zhang Y, Shen T, Zhou S, Wang W, Lin S, Zhu G. pH-Responsive STING-Activating DNA Nanovaccines for Cancer Immunotherapy. Adv Ther (Weinh). 2020;3. 10.1002/adtp.202000083 34337143 10.1002/adtp.202000083 PMC8323737

142. Goradel NH Negahdari B Mohajel N Malekshahi ZV Shirazi MMA Arashkia A Heterologous administration of HPV16 E7 epitope-loaded nanocomplexes inhibits tumor growth in mouse model Int Immunopharmacol 2021 10.1016/j.intimp.2021.108298 34739928 Goradel NH, Negahdari B, Mohajel N, Malekshahi ZV, Shirazi MMA, Arashkia A. Heterologous administration of HPV16 E7 epitope-loaded nanocomplexes inhibits tumor growth in mouse model. Int Immunopharmacol. 2021;101.10.1016/j.intimp.2021.108298 34739928 10.1016/j.intimp.2021.108298

143. Wang Y, Chen X, Tian B, Liu J, Yang L, Zeng L, et al. Nucleolin-targeted extracellular vesicles as a versatile platform for biologics delivery to breast cancer. Theranostics. 2017;7. 10.7150/thno.16532 PMC5399599 28435471

144. Yuan ZQ Kolluri KK Gowers KHC Janes SM Trail delivery by MSC-derived extracellular vesicles is an effective anticancer therapy J Extracell Vesicles 2017 10.1080/20013078.2017.1265291 28326166 PMC5328331 Yuan ZQ, Kolluri KK, Gowers KHC, Janes SM. TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy. J Extracell Vesicles. 2017;6. 10.1080/20013078.2017.1265291 28326166 10.1080/20013078.2017.1265291 PMC5328331

145. Ma J Zhang Y Tang K Zhang H Yin X Li Y Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles Cell Res 2016 10.1038/cr.2016.53 27167569 PMC4897183 Ma J, Zhang Y, Tang K, Zhang H, Yin X, Li Y, et al. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles. Cell Res. 2016;26. 10.1038/cr.2016.53 27167569 10.1038/cr.2016.53 PMC4897183

146. Morishita M Takahashi Y Matsumoto A Nishikawa M Takakura Y Exosome-based tumor antigens–adjuvant codelivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA Biomaterials 2016 10.1016/j.biomaterials.2016.09.031 27723556 Morishita M, Takahashi Y, Matsumoto A, Nishikawa M, Takakura Y. Exosome-based tumor antigens–adjuvant codelivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA. Biomaterials. 2016;111.10.1016/j.biomaterials.2016.09.031 27723556 10.1016/j.biomaterials.2016.09.031

147. Liang Q, Bie N, Yong T, Tang K, Shi X, Wei Z, et al. The softness of tumor-cell-derived microparticles regulates their drug-delivery efficiency. Nat Biomed Eng. 2019;3. 10.1038/s41551-019-0405-4 31110292

148. Ohno SI Takanashi M Sudo K Ueda S Ishikawa A Matsuyama N Systemically injected exosomes targeted to EGFR deliver antitumor microrna to breast cancer cells Mol Ther 2013 10.1038/mt.2012.180 23032975 PMC3538304 Ohno SI, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microrna to breast cancer cells. Molecular Therapy. 2013;21.10.1038/mt.2012.180 23032975 10.1038/mt.2012.180 PMC3538304

149. Kooijmans SAA, Aleza CG, Roffler SR, van Solinge WW, Vader P, Schiffelers RM. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumor cell targeting. J Extracell Vesicles. 2016;5. 10.3402/jev.v5.31053 PMC4793259 26979463

150. Tang K, Zhang Y, Zhang H, Xu P, Liu J, Ma J, et al. Delivery of chemotherapeutic drugs in tumor cell-derived microparticles. Nat Commun. 2012;3. 10.1038/ncomms2282 23250412

151. Phuengkham H Song C Um SH Lim YT Implantable synthetic immune niche for spatiotemporal modulation of tumor-derived immunosuppression and systemic antitumor immunity: postoperative immunotherapy Adv Mater 2018 10.1002/adma.201706719 29572968 Phuengkham H, Song C, Um SH, Lim YT. Implantable Synthetic Immune Niche for Spatiotemporal Modulation of Tumor-Derived Immunosuppression and Systemic Antitumor Immunity: Postoperative Immunotherapy. Advanced Materials. 2018;30. 10.1002/adma.201706719 29572968 10.1002/adma.201706719

152. Ali OA Huebsch N Cao L Dranoff G Mooney DJ Infection-mimicking materials to program dendritic cells in situ Nat Mater 2009 10.1038/nmat2357 19136947 PMC2684978 Ali OA, Huebsch N, Cao L, Dranoff G, Mooney DJ. Infection-mimicking materials to program dendritic cells in situ. Nat Mater. 2009;8.10.1038/nmat2357 19136947 10.1038/nmat2357 PMC2684978

153. Ahn YH, Ren L, Kim SM, Seo SH, Jung CR, Kim DS, et al. A three-dimensional hyaluronic acid-based niche enhances the therapeutic efficacy of human natural killer cell-based cancer immunotherapy. Biomaterials. 2020;247. 10.1016/j.biomaterials.2020.119960 32278822

154. Li Y Fang M Zhang J Wang J Song Y Shi J Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity Oncoimmunology 2016 10.1080/2162402X.2015.1074374 27057439 PMC4801446 Li Y, Fang M, Zhang J, Wang J, Song Y, Shi J, et al. Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity. Oncoimmunology. 2016;5.10.1080/2162402X.2015.1074374 27057439 10.1080/2162402X.2015.1074374 PMC4801446

155. Song H Huang P Niu J Shi G Zhang C Kong D Injectable polypeptide hydrogel for dual-delivery of antigen and TLR3 agonist to modulate dendritic cells in vivo and enhance potent cytotoxic T-lymphocyte response against melanoma Biomaterials 2018 10.1016/j.biomaterials.2018.01.004 29324304 Song H, Huang P, Niu J, Shi G, Zhang C, Kong D, et al. Injectable polypeptide hydrogel for dual-delivery of antigen and TLR3 agonist to modulate dendritic cells in vivo and enhance potent cytotoxic T-lymphocyte response against melanoma. Biomaterials. 2018;159.10.1016/j.biomaterials.2018.01.004 29324304 10.1016/j.biomaterials.2018.01.004

156. Wang C Wang J Zhang X Yu S Wen D Hu Q In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy Sci Transl Med 2018 10.1126/scitranslmed.aan3682 29467299 Wang C, Wang J, Zhang X, Yu S, Wen D, Hu Q, et al. In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy. Sci Transl Med. 2018;10.10.1126/scitranslmed.aan3682 29467299 10.1126/scitranslmed.aan3682

157. Xie X Wang H Williams GR Yang Y Zheng Y Wu J Erythrocyte membrane cloaked curcumin-loaded nanoparticles for enhanced chemotherapy Pharmaceutics 2019 10.3390/pharmaceutics11090429 31450749 PMC6781301 Xie X, Wang H, Williams GR, Yang Y, Zheng Y, Wu J, et al. Erythrocyte membrane cloaked curcumin-loaded nanoparticles for enhanced chemotherapy. Pharmaceutics. 2019;11.10.3390/pharmaceutics11090429 31450749 10.3390/pharmaceutics11090429 PMC6781301

158. Zhang L, Wang Z, Zhang Y, Cao F, Dong K, Ren J, et al. Erythrocyte membrane cloaked metal-organic framework nanoparticle as biomimetic nanoreactor for starvation-activated colon cancer therapy. ACS Nano. 2018;12. 10.1021/acsnano.8b05200 30265804

159. Luk BT, Fang RH, Hu CMJ, Copp JA, Thamphiwatana S, Dehaini D, et al. Safe and immunocompatible nanocarriers cloaked in RBC membranes for drug delivery to treat solid tumors. Theranostics. 2016;6. 10.7150/thno.14471 PMC4876624 27217833

160. Zhang L, Li R, Chen H, Wei J, Qian H, Su S, et al. Human cytotoxic T-lymphocyte membrane-camouflaged nanoparticles combined with low-dose irradiation: a new approach to enhance drug targeting in gastric cancer. Int J Nanomedicine. 2017;12. 10.2147/IJN.S126016 PMC5364008 28360520

161. Deng G Sun Z Li S Peng X Li W Zhou L Cell-membrane immunotherapy based on natural killer cell membrane coated nanoparticles for the effective inhibition of primary and abscopal tumor growth ACS Nano 2018 10.1021/acsnano.8b05292 30444351 Deng G, Sun Z, Li S, Peng X, Li W, Zhou L, et al. Cell-Membrane Immunotherapy Based on Natural Killer Cell Membrane Coated Nanoparticles for the Effective Inhibition of Primary and Abscopal Tumor Growth. ACS Nano. 2018;12.10.1021/acsnano.8b05292 30444351 10.1021/acsnano.8b05292

162. Sridhar P Petrocca F Regional delivery of chimeric antigen receptor (CAR) T cells for cancer therapy Cancers (Basel) 2017 10.3390/cancers9070092 28718815 PMC5532628 Sridhar P, Petrocca F. Regional delivery of chimeric antigen receptor (CAR) T cells for cancer therapy. Cancers (Basel). 2017.10.3390/cancers9070092 28718815 10.3390/cancers9070092 PMC5532628

163. Cheng Z Li M Dey R Chen Y Nanomaterials for cancer therapy: current progress and perspectives J Hematol Oncol 2021 10.1186/s13045-021-01096-0 34059100 PMC8165984 Cheng Z, Li M, Dey R, Chen Y. Nanomaterials for cancer therapy: current progress and perspectives. J Hematol Oncol. 2021.10.1186/s13045-021-01096-0 34059100 10.1186/s13045-021-01096-0 PMC8165984

164. Waheed S Li Z Zhang F Chiarini A Armato U Wu J Engineering nanodrug biointerface to overcome biological barriers toward precision drug delivery J Nanobiotechnol 2022 10.1186/s12951-022-01605-4 PMC9428887 36045386 Waheed S, Li Z, Zhang F, Chiarini A, Armato U, Wu J. Engineering nanodrug biointerface to overcome biological barriers toward precision drug delivery. J Nanobiotechnology. 2022. 10.1186/s12951-022-01605-4 10.1186/s12951-022-01605-4 PMC9428887 36045386

165. Zhou Y Chen X Cao J Gao H Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy J Mater Chem B 2020 10.1039/D0TB00649A 32315375 Zhou Y, Chen X, Cao J, Gao H. Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy. J Mater Chem B. 2020.10.1039/D0TB00649A 32315375 10.1039/d0tb00649a

166. Hosseini M, Haji-Fatahaliha M, Jadidi-Niaragh F, Majidi J, Yousefi M. The use of nanoparticles as a promising therapeutic approach in cancer immunotherapy. Artif Cells Nanomed Biotechnol. 2016;44. 10.3109/21691401.2014.998830 25612903

167. Yao Y Zhou Y Liu L Xu Y Chen Q Wang Y Nanoparticle-based drug delivery in cancer therapy and its role in overcoming drug resistance Front Mol Biosci 2020 10.3389/fmolb.2020.00193 32974385 PMC7468194 Yao Y, Zhou Y, Liu L, Xu Y, Chen Q, Wang Y, et al. Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance. Front Mol Biosci. 2020. 10.3389/fmolb.2020.00193 32974385 10.3389/fmolb.2020.00193 PMC7468194

168. Cheng YH He C Riviere JE Monteiro-Riviere NA Lin Z Meta-analysis of nanoparticle delivery to tumors using a physiologically based pharmacokinetic modeling and simulation approach ACS Nano 2020 10.1021/acsnano.9b08142 32078303 PMC7098057 Cheng YH, He C, Riviere JE, Monteiro-Riviere NA, Lin Z. Meta-Analysis of Nanoparticle Delivery to Tumors Using a Physiologically Based Pharmacokinetic Modeling and Simulation Approach. ACS Nano. 2020;14. 10.1021/acsnano.9b08142 32078303 10.1021/acsnano.9b08142 PMC7098057

169. Pudlarz A Szemraj J Nanoparticles as carriers of proteins, peptides and other therapeutic molecules Open Life Sci 2018 10.1515/biol-2018-0035 33817095 PMC7874720 Pudlarz A, Szemraj J. Nanoparticles as carriers of proteins, peptides and other therapeutic molecules. Open Life Sci. 2018.10.1515/biol-2018-0035 33817095 10.1515/biol-2018-0035 PMC7874720

170. Shinde VR Revi N Murugappan S Singh SP Rengan AK Enhanced permeability and retention effect: a key facilitator for solid tumor targeting by nanoparticles Photodiagnosis Photodyn Ther 2022 10.1016/j.pdpdt.2022.102915 35597441 Shinde VR, Revi N, Murugappan S, Singh SP, Rengan AK. Enhanced permeability and retention effect: A key facilitator for solid tumor targeting by nanoparticles. Photodiagnosis Photodyn Ther. 2022. 10.1016/j.pdpdt.2022.102915 35597441 10.1016/j.pdpdt.2022.102915

171. Wang H, Li Z, Lu S, Li C, Zhao W, Zhao Y, et al. Nano micelles of cellulose-graft-poly (L-lactic acid) anchored with epithelial cell adhesion antibody for enhanced drug loading and anti-tumor effect. Mater Today, Commun. 2020;22.

172. Badrinath N Jeong YI Woo HY Bang SY Kim C Heo J Local delivery of a cancer-favoring oncolytic vaccinia virus via poly (lactic-co-glycolic acid) nanofiber for theranostic purposes Int J Pharm 2018 10.1016/j.ijpharm.2018.10.020 30308276 Badrinath N, Jeong Y Il, Woo HY, Bang SY, Kim C, Heo J, et al. Local delivery of a cancer-favoring oncolytic vaccinia virus via poly (lactic-co-glycolic acid) nanofiber for theranostic purposes. Int J Pharm. 2018;552. 10.1016/j.ijpharm.2018.10.020 30308276 10.1016/j.ijpharm.2018.10.020

173. Chiang CS Lin YJ Lee R Lai YH Cheng HW Hsieh CH Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumor-localized immunotherapy Nat Nanotechnol 2018 10.1038/s41565-018-0146-7 29760523 Chiang CS, Lin YJ, Lee R, Lai YH, Cheng HW, Hsieh CH, et al. Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumor-localized immunotherapy. Nat Nanotechnol. 2018;13. 10.1038/s41565-018-0146-7 29760523 10.1038/s41565-018-0146-7

174. Mohapatra A Sathiyamoorthy P Park IK Metallic nanoparticle-mediated immune cell regulation and advanced cancer immunotherapy Pharmaceutics 2021 10.3390/pharmaceutics13111867 34834282 PMC8622235 Mohapatra A, Sathiyamoorthy P, Park IK. Metallic nanoparticle-mediated immune cell regulation and advanced cancer immunotherapy. Pharmaceutics. 2021. 10.3390/pharmaceutics13111867 34834282 10.3390/pharmaceutics13111867 PMC8622235

175. Xu J Lv J Zhuang Q Yang Z Cao Z Xu L A general strategy toward personalized nanovaccines based on fluoropolymers for postsurgical cancer immunotherapy Nat Nanotechnol 2020 10.1038/s41565-020-00781-4 33139933 Xu J, Lv J, Zhuang Q, Yang Z, Cao Z, Xu L, et al. A general strategy toward personalized nanovaccines based on fluoropolymers for postsurgical cancer immunotherapy. Nat Nanotechnol. 2020;15. 10.1038/s41565-020-00781-4 33139933 10.1038/s41565-020-00781-4

176. Luo Z, He T, Liu P, Yi Z, Zhu S, Liang X, et al. Self-adjuvanted molecular activator (SeaMac) nanovaccines promote cancer immunotherapy. Adv Healthc Mater. 2021;10. 10.1002/adhm.202002080 33336537

177. Wang J Wu X Shen P Wang J Shen Y Shen Y Applications of inorganic nanomaterials in photothermal therapy based on combinational cancer treatment Int J Nanomedicine 2020 10.2147/IJN.S239751 32256067 PMC7094149 Wang J, Wu X, Shen P, Wang J, Shen Y, Shen Y, et al. Applications of inorganic nanomaterials in photothermal therapy based on combinational cancer treatment. Int J Nanomedicine. 2020. 10.2147/IJN.S239751 32256067 10.2147/IJN.S239751 PMC7094149

178. Montaseri H Kruger CA Abrahamse H Organic nanoparticle based active targeting for photodynamic therapy treatment of breast cancer cells Oncotarget 2020 10.18632/oncotarget.27596 32547709 PMC7275783 Montaseri H, Kruger CA, Abrahamse H. Review: Organic nanoparticle based active targeting for photodynamic therapy treatment of breast cancer cells. Oncotarget. 2020. 10.18632/oncotarget.27596 32547709 10.18632/oncotarget.27596 PMC7275783

179. Kim J Chun SH Amornkitbamrung L Song C Yuk JS Ahn SY Gold nanoparticle clusters for the investigation of therapeutic efficiency against prostate cancer under near-infrared irradiation Nano Convergence 2020 10.1186/s40580-019-0216-z 32064551 PMC7024685 Kim J, Chun SH, Amornkitbamrung L, Song C, Yuk JS, Ahn SY, et al. Gold nanoparticle clusters for the investigation of therapeutic efficiency against prostate cancer under near-infrared irradiation. Nano Converg. 2020;7.10.1186/s40580-019-0216-z 32064551 10.1186/s40580-019-0216-z PMC7024685

180. Lu Z, Bai S, Jiang Y, Wu S, Xu D, Zhang J, et al. Amplifying dendritic cell activation by bioinspired nanometal organic frameworks for synergistic sonoimmunotherapy. Small. 2022;18. 10.1002/smll.202203952 36148843

181. Lim S Park J Shim MK Um W Yoon HY Ryu JH Recent advances and challenges of repurposing nanoparticle-based drug delivery systems to enhance cancer immunotherapy Theranostics 2019 10.7150/thno.38425 31695807 PMC6831456 Lim S, Park J, Shim MK, Um W, Yoon HY, Ryu JH, et al. Recent advances and challenges of repurposing nanoparticle-based drug delivery systems to enhance cancer immunotherapy. Theranostics. 2019. 10.7150/thno.38425 31695807 10.7150/thno.38425 PMC6831456

182. Cai L Xu J Yang Z Tong R Dong Z Wang C Engineered biomaterials for cancer immunotherapy MedComm 2020 10.1002/mco2.8 34766108 PMC8489675 Cai L, Xu J, Yang Z, Tong R, Dong Z, Wang C, et al. Engineered biomaterials for cancer immunotherapy. MedComm (Beijing). 2020.10.1002/mco2.8 34766108 10.1002/mco2.8 PMC8489675

183. Ren L Lim YT Degradation-regulatable architectured implantable macroporous scaffold for the spatiotemporal modulation of immunosuppressive microenvironment and enhanced combination cancer immunotherapy Adv Funct Mater 2018 10.1002/adfm.201804490 Ren L, Lim YT. Degradation-Regulatable Architectured Implantable Macroporous Scaffold for the Spatiotemporal Modulation of Immunosuppressive Microenvironment and Enhanced Combination Cancer Immunotherapy. Adv Funct Mater. 2018;28.10.1002/adfm.20180449034084100

184. Li J Luo Y Li B Xia Y Wang H Fu C Implantable and injectable biomaterial scaffolds for cancer immunotherapy Front Bioeng Biotechnol 2020 10.3389/fbioe.2020.612950 33330440 PMC7734317 Li J, Luo Y, Li B, Xia Y, Wang H, Fu C. Implantable and Injectable Biomaterial Scaffolds for Cancer Immunotherapy. Front Bioeng Biotechnol. 2020. 10.3389/fbioe.2020.612950 33330440 10.3389/fbioe.2020.612950 PMC7734317

185. Cai MH Chen XY Fu LQ Du WL Yang X Mou XZ Design and development of hybrid hydrogels for biomedical applications: recent trends in anticancer drug delivery and tissue engineering Front Bioeng Biotechnol 2021 10.3389/fbioe.2021.630943 33681168 PMC7925894 Cai MH, Chen XY, Fu LQ, Du WL, Yang X, Mou XZ, et al. Design and Development of Hybrid Hydrogels for Biomedical Applications: Recent Trends in Anticancer Drug Delivery and Tissue Engineering. Front Bioeng Biotechnol. 2021. 10.3389/fbioe.2021.630943 33681168 10.3389/fbioe.2021.630943 PMC7925894

186. Liu M, Cao Z, Zhang R, Chen Y, Yang X. Injectable supramolecular hydrogel for locoregional immune checkpoint blockade and enhanced cancer chemo-immunotherapy. ACS Appl Mater Interfaces. 2021;13. 10.1021/acsami.1c08285 34275267

187. Kalluri R LeBleu VS The biology, function, and biomedical applications of exosomes Science 2020 10.1126/science.aau6977 32029601 PMC7717626 Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science (1979). 2020.10.1126/science.aau6977 32029601 10.1126/science.aau6977 PMC7717626

188. Li S Xu J Qian J Gao X Engineering extracellular vesicles for cancer therapy: recent advances and challenges in clinical translation Biomater Sci 2020 10.1039/D0BM01385D 33155579 Li S, Xu J, Qian J, Gao X. Engineering extracellular vesicles for cancer therapy: Recent advances and challenges in clinical translation. Biomater Sci. 2020.10.1039/D0BM01385D 33155579 10.1039/d0bm01385d

189. Elliott RO He M Unlocking the power of exosomes for crossing biological barriers in drug delivery Pharmaceutics 2021 10.3390/pharmaceutics13010122 33477972 PMC7835896 Elliott RO, He M. Unlocking the power of exosomes for crossing biological barriers in drug delivery. Pharmaceutics. 2021.10.3390/pharmaceutics13010122 33477972 10.3390/pharmaceutics13010122 PMC7835896

190. Wang J Li W Zhang L Ban L Chen P Du W Chemically edited exosomes with dual ligand purified by microfluidic device for active targeted drug delivery to tumor cells ACS Appl Mater Interfaces 2017 10.1021/acsami.7b06464 28762264 Wang J, Li W, Zhang L, Ban L, Chen P, Du W, et al. Chemically Edited Exosomes with Dual Ligand Purified by Microfluidic Device for Active Targeted Drug Delivery to Tumor Cells. ACS Appl Mater Interfaces. 2017;9.10.1021/acsami.7b06464 28762264 10.1021/acsami.7b06464

191. Zitvogel L Regnault A Lozier A Wolfers J Flament C Tenza D Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes Nat Med 1998 10.1038/nm0598-594 9585234 Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes. Nat Med. 1998;4. 10.1038/nm0598-594 9585234 10.1038/nm0598-594

192. Jia G Han Y An Y Ding Y He C Wang X NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo Biomaterials 2018 10.1016/j.biomaterials.2018.06.029 29982104 Jia G, Han Y, An Y, Ding Y, He C, Wang X, et al. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo Biomaterials 10.1016/j.biomaterials.2018.06.029 29982104 10.1016/j.biomaterials.2018.06.029

193. Abou-El-Enein M Elsallab M Feldman SA Fesnak AD Heslop HE Marks P Scalable manufacturing of CAR T cells for cancer immunotherapy Blood Cancer Discov 2021 10.1158/2643-3230.BCD-21-0084 34568831 PMC8462122 Abou-El-Enein M, Elsallab M, Feldman SA, Fesnak AD, Heslop HE, Marks P, et al. Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy. Blood Cancer Discov. 2021. 10.1158/2643-3230.BCD-21-0084 34568831 10.1158/2643-3230.BCD-21-0084 PMC8462122

194. Liu Y Yan X Zhang F Zhang X Tang F Han Z TCR-T immunotherapy: the challenges and solutions Front Oncol 2022 10.3389/fonc.2021.794183 35145905 PMC8822241 Liu Y, Yan X, Zhang F, Zhang X, Tang F, Han Z, et al. TCR-T Immunotherapy: The Challenges and Solutions. Front Oncol. 2022. 10.3389/fonc.2021.794183 35145905 10.3389/fonc.2021.794183 PMC8822241

195. Labanieh L Majzner RG Mackall CL Programming CAR-T cells to kill cancer Nat Biomed Eng 2018 10.1038/s41551-018-0235-9 31011197 Labanieh L, Majzner RG, Mackall CL. Programming CAR-T cells to kill cancer. Nat Biomed Eng. 2018.10.1038/s41551-018-0235-9 31011197 10.1038/s41551-018-0235-9

196. Grosskopf AK, Labanieh L, Klysz DD, Roth GA, Xu P, Adebowale O, et al. Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. Sci Adv. 2022;8.10.1126/sciadv.abn8264 10.1126/sciadv.abn8264 PMC8993118 35394838

197. Hu Q, Li H, Archibong E, Chen Q, Ruan H, Ahn S, et al. Inhibition of postsurgery tumor recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets. Nat Biomed Eng. 2021;5. 10.1038/s41551-021-00712-1 PMC9102991 33903744

198. Stephan SB Taber AM Jileaeva I Pegues EP Sentman CL Stephan MT Biopolymer implants enhance the efficacy of adoptive T-cell therapy Nat Biotechnol 2015 10.1038/nbt.3104 25503382 PMC4289408 Stephan SB, Taber AM, Jileaeva I, Pegues EP, Sentman CL, Stephan MT. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat Biotechnol. 2015;33.10.1038/nbt.3104 25503382 10.1038/nbt.3104 PMC4289408

199. Sadozai H Gruber T Hunger RE Schenk M Recent successes and future directions in immunotherapy of cutaneous melanoma Front Immunol 2017 10.3389/fimmu.2017.01617 29276510 PMC5727014 Sadozai H, Gruber T, Hunger RE, Schenk M. Recent successes and future directions in immunotherapy of cutaneous melanoma. Front Immunol. 2017.10.3389/fimmu.2017.01617 29276510 10.3389/fimmu.2017.01617 PMC5727014

200. Johnson DB Peng C Sosman JA Nivolumab in melanoma: latest evidence and clinical potential Ther Adv Med Oncol 2015 10.1177/1758834014567469 25755682 PMC4346215 Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: Latest evidence and clinical potential. Ther Adv Med Oncol. 2015.10.1177/1758834014567469 25755682 10.1177/1758834014567469 PMC4346215

201. Krzyżanowska N Krawczyk P Wojas-Krawczyk K Kucharczyk T Milanowski J Immunotherapy in non-small cell lung cancer patients with driver alterations: a new strategy? Cells 2022 10.3390/cells11203280 36291146 PMC9600960 Krzyżanowska N, Krawczyk P, Wojas-Krawczyk K, Kucharczyk T, Milanowski J. Immunotherapy in Non-Small Cell Lung Cancer Patients with Driver Alterations: A New Strategy? Cells. 2022. 10.3390/cells11203280 36291146 10.3390/cells11203280 PMC9600960

202. Ren X Li Y Nishimura C Zang X Crosstalk between the B7/CD28 and EGFR pathways: mechanisms and therapeutic opportunities Genes Dis 2022 10.1016/j.gendis.2021.08.009 35873032 PMC9293717 Ren X, Li Y, Nishimura C, Zang X. Crosstalk between the B7/CD28 and EGFR pathways: Mechanisms and therapeutic opportunities. Genes Dis. 2022. 10.1016/j.gendis.2021.08.009 35873032 10.1016/j.gendis.2021.08.009 PMC9293717

203. Lizardo DY Kuang C Hao S Yu J Huang Y Zhang L Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: from bench to bedside Biochim Biophys Acta Rev Cancer 2020 10.1016/j.bbcan.2020.188447 33035640 PMC7886024 Lizardo DY, Kuang C, Hao S, Yu J, Huang Y, Zhang L. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside. Biochim Biophys Acta Rev Cancer. 2020. 10.1016/j.bbcan.2020.188447 33035640 10.1016/j.bbcan.2020.188447 PMC7886024

204. Ganesh K Stadler ZK Cercek A Mendelsohn RB Shia J Segal NH Immunotherapy in colorectal cancer: rationale, challenges and potential Nat Rev Gastroenterol Hepatol 2019 10.1038/s41575-019-0126-x 30886395 PMC7295073 Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019.10.1038/s41575-019-0126-x 30886395 10.1038/s41575-019-0126-x PMC7295073

205. Zhang X Ge X Jiang T Yang R Li S Research progress on immunotherapy in triple-negative breast cancer (review) Int J Oncol 2022 10.3892/ijo.2022.5385 35762339 PMC9256074 Zhang X, Ge X, Jiang T, Yang R, Li S. Research progress on immunotherapy in triple negative breast cancer (Review). Int J Oncol. 2022.10.3892/ijo.2022.5385 35762339 10.3892/ijo.2022.5385 PMC9256074

206. Wang X Qi Y Kong X Zhai J Li Y Song Y Immunological therapy: a novel thriving area for triple-negative breast cancer treatment Cancer Lett 2019 10.1016/j.canlet.2018.10.042 30419345 Wang X, Qi Y, Kong X, Zhai J, Li Y, Song Y, et al. Immunological therapy: A novel thriving area for triple-negative breast cancer treatment. Cancer Lett. 2019.10.1016/j.canlet.2018.10.042 30419345 10.1016/j.canlet.2018.10.042

207. Maselli FM Giuliani F Laface C Perrone M Melaccio A De Santis P Immunotherapy in prostate cancer: state of art and new therapeutic perspectives Curr Oncol 2023 10.3390/curroncol30060432 37366915 PMC10297468 Maselli FM, Giuliani F, Laface C, Perrone M, Melaccio A, De Santis P, et al. Immunotherapy in Prostate Cancer: State of Art and New Therapeutic Perspectives. Current Oncology. 2023. 10.3390/curroncol30060432 37366915 10.3390/curroncol30060432 PMC10297468

208. Mendoza AA, Martin FV, Avalos JA, Valls TJO, Jimenez HMV, Perea EB. Advancements in glioblastoma management: a comprehensive review of therapeutic strategies and future directions. International Journal of Medical Science and Clinical Research Studies. 2023;03.

209. Konecny GE Kristeleit RS PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions Br J Cancer 2016 10.1038/bjc.2016.311 27736844 PMC5104889 Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: Current practice and future directions. Br J Cancer. 2016. 10.1038/bjc.2016.311 27736844 10.1038/bjc.2016.311 PMC5104889

210. Gibney GT Weiner LM Atkins MB Predictive biomarkers for checkpoint inhibitor-based immunotherapy Lancet Oncol 2016 10.1016/S1470-2045(16)30406-5 27924752 PMC5702534 Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016.10.1016/S1470-2045(16)30406-5 27924752 10.1016/S1470-2045(16)30406-5 PMC5702534

211. Incorvaia L Fanale D Badalamenti G Barraco N Bono M Corsini LR Programmed death ligand 1 (PD-L1) as a predictive biomarker for pembrolizumab therapy in patients with advanced non-small cell lung cancer (NSCLC) Adv Ther 2019 10.1007/s12325-019-01057-7 31432460 PMC6822831 Incorvaia L, Fanale D, Badalamenti G, Barraco N, Bono M, Corsini LR, et al. Programmed Death Ligand 1 (PD-L1) as a Predictive Biomarker for Pembrolizumab Therapy in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC). Adv Ther. 2019.10.1007/s12325-019-01057-7 31432460 10.1007/s12325-019-01057-7 PMC6822831

212. Barroso-Sousa R Pacífico JP Sammons S Tolaney SM Tumor mutational burden in breast cancer: current evidence, challenges, and opportunities Cancers (Basel) 2023 10.3390/cancers15153997 37568813 PMC10417019 Barroso-Sousa R, Pacífico JP, Sammons S, Tolaney SM. Tumor Mutational Burden in Breast Cancer: Current Evidence, Challenges, and Opportunities. Cancers (Basel). 2023. 10.3390/cancers15153997 37568813 10.3390/cancers15153997 PMC10417019

213. Maleki Vareki S Garrigós C Duran I Biomarkers of response to PD-1/PD-L1 inhibition Crit Rev Oncol Hematol 2017 10.1016/j.critrevonc.2017.06.001 28693793 Maleki Vareki S, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev Oncol Hematol. 2017.10.1016/j.critrevonc.2017.06.001 28693793 10.1016/j.critrevonc.2017.06.001

214. Remon J Collazo A Jimenez B Checkmate 227 trial has not checked the immune-strategy in first-line setting in advanced non-small cell lung cancer Transl Cancer Res 2020 10.21037/tcr.2020.03.09 35117575 PMC8797323 Remon J, Collazo A, Jimenez B. CheckMate 227 trial has not checked the immune-strategy in first-line setting in advanced non-small cell lung cancer. Transl Cancer Res. 2020.10.21037/tcr.2020.03.09 35117575 10.21037/tcr.2020.03.09 PMC8797323

215. Ooki A Osumi H Yoshino K Yamaguchi K Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair Gastric Cancer 2024 27 907 931 10.1007/s10120-024-01523-4 38922524 PMC11335850 Ooki A, Osumi H, Yoshino K, Yamaguchi K. 2024 Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair Gastric Cancer. 2024;27:907–3110.1007/s10120-024-01523-4 38922524 10.1007/s10120-024-01523-4 PMC11335850

216. Versluis JM Blankenstein S Dimitriadis P Sanders J Hoefakker W Broeks A The prognostic value of the interferon-gamma (IFNγ) signature in patients with macroscopic stage III melanoma treated with and without adjuvant systemic therapy J Clin Oncol 2021 10.1200/JCO.2021.39.15_suppl.9579 Versluis JM, Blankenstein S, Dimitriadis P, Sanders J, Hoefakker W, Broeks A, et al. The prognostic value of the interferon-gamma (IFNγ) signature in patients with macroscopic stage III melanoma treated with and without adjuvant systemic therapy J Clin Oncol 10.1200/JCO.2021.39.15_suppl.957933434075

217. Porciello N, Franzese O, D’Ambrosio L, Palermo B, Nisticò P. T-cell repertoire diversity: friend or foe for protective antitumor response? Journal of Experimental and Clinical Cancer Research. 2022. 10.1186/s13046-022-02566-0 PMC9773533 36550555

218. Garassino MC Gadgeel S Speranza G Felip E Esteban E Dómine M Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study J Clin Oncol 2023 10.1200/jco.22.01989 36809080 PMC10082311 Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small Cell Lung Cancer: 5-Year Outcomes from the Phase 3 KEYNOTE-189 Study. Journal of Clinical Oncology. 2023;41.10.1200/jco.22.01989 36809080 10.1200/JCO.22.01989 PMC10082311

219. Emens LA Molinero L Loi S Rugo HS Schneeweiss A Diéras V Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer: biomarker evaluation of the IMpassion130 study J Natl Cancer Inst 2021 10.1093/jnci/djab004 33523233 PMC8328980 Emens LA, Molinero L, Loi S, Rugo HS, Schneeweiss A, Diéras V, et al. Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study. J Natl Cancer Inst. 2021;113.10.1093/jnci/djab004 33523233 10.1093/jnci/djab004 PMC8328980

220. Janjigian YY Ajani JA Moehler M Shen L Garrido M Gallardo C First-line Nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the phase III CheckMate 649 trial J Clin Oncol 2024 10.1200/JCO.23.01601 38382001 PMC11185916 Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, et al. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. Journal of Clinical Oncology. 2024;42. 10.1200/JCO.23.01601 38382001 10.1200/JCO.23.01601 PMC11185916

221. Choueiri TK, Penkov K, Uemura H, Campbell MT, Pal S, Kollmannsberger C, et al. Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase III JAVELIN Renal 101 trial. Annals of Oncology [Internet]. 2025;36:387–92. Available from: https://www.sciencedirect.com/science/article/pii/S0923753424049871 10.1016/j.annonc.2024.12.008 PMC12184433 39706335

222. Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. Journal of Clinical Oncology. 2024;42. 10.1200/JCO.23.01569 PMC11095851 38227898

223. Tawbi HA Robert C Brase JC Gusenleitner D Gasal E Garrett J Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i) J Immunother Cancer 2022 10.1136/jitc-2021-004226 35728875 PMC9214378 Tawbi HA, Robert C, Brase JC, Gusenleitner D, Gasal E, Garrett J, et al. Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i). J Immunother Cancer. 2022;10.10.1136/jitc-2021-004226 35728875 10.1136/jitc-2021-004226 PMC9214378

224. Kudo M, Finn RS, Galle PR, Zhu AX, Ducreux M, Cheng AL, et al. IMbrave150: efficacy and safety of atezolizumab plus bevacizumab versus sorafenib in patients with barcelona clinic liver cancer stage b unresectable hepatocellular carcinoma: an exploratory analysis of the phase III study. Liver Cancer. 2023;12. 10.1159/000528272 PMC10521324 37767068

225. Theelen WSME, Peulen HMU, Lalezari F, Van Der Noort V, De Vries JF, Aerts JGJV, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol. 2019;5. 10.1001/jamaoncol.2019.1478 PMC6624814 31294749

226. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: Results from an open-label, multicenter phase i/ii study. Annals of Oncology. 2013;24. 10.1093/annonc/mdt107 PMC3707423 23535954

227. Derosa L Routy B Thomas AM Iebba V Zalcman G Friard S Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small cell lung cancer Nat Med 2022 10.1038/s41591-021-01655-5 35115705 PMC9330544 Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small cell lung cancer. Nat Med. 2022;28.10.1038/s41591-021-01655-5 35115705 10.1038/s41591-021-01655-5 PMC9330544

228. Borgers JSW Burgers FH Terveer EM van Leerdam ME Korse CM Kessels R Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial BMC Cancer 2022 10.1186/s12885-022-10457-y 36585700 PMC9801532 Borgers JSW, Burgers FH, Terveer EM, van Leerdam ME, Korse CM, Kessels R, et al. Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial. BMC Cancer. 2022;22.10.1186/s12885-022-10457-y 36585700 10.1186/s12885-022-10457-y PMC9801532

229. Li Q, Li Y, Wang Y, Xu L, Guo Y, Wang Y, et al. Oral administration of Bifidobacterium breve promotes antitumor efficacy via dendritic cells-derived interleukin 12. Oncoimmunology. 2021;10. 10.1080/2162402X.2020.1868122 PMC7833736 33537172

230. Guven DC Kavgaci G Erul E Syed MP Magge T Saeed A The efficacy of immune checkpoint inhibitors in microsatellite stable colorectal cancer: a systematic review Oncologist 2024 10.1093/oncolo/oyae013 38309719 PMC11067816 Guven DC, Kavgaci G, Erul E, Syed MP, Magge T, Saeed A, et al. The Efficacy of Immune Checkpoint Inhibitors in Microsatellite Stable Colorectal Cancer: A Systematic Review. Oncologist. 2024.10.1093/oncolo/oyae013 38309719 10.1093/oncolo/oyae013 PMC11067816

231. Kim K, Lee M, Shin Y, Lee Y, Kim T-J. Optimizing cancer treatment through gut microbiome modulation. Cancers (Basel) [Internet]. 2025;17. Available from: https://www.mdpi.com/2072-6694/17/7/1252 10.3390/cancers17071252 PMC11988035 40227841

232. Shvets Y Khranovska N Senchylo N Ostapchenko D Tymoshenko I Onysenko S Microbiota substances modulate dendritic cells activity: a critical view Heliyon 2024 10.1016/j.heliyon.2024.e27125 38444507 PMC10912702 Shvets Y, Khranovska N, Senchylo N, Ostapchenko D, Tymoshenko I, Onysenko S, et al. Microbiota substances modulate dendritic cells activity: A critical view. Heliyon. 2024.10.1016/j.heliyon.2024.e27125 38444507 10.1016/j.heliyon.2024.e27125 PMC10912702

233. Park R Umar S Kasi A Immunotherapy in colorectal cancer: potential of fecal transplant and microbiota-augmented clinical trials Curr Colorectal Cancer Rep 2020 10.1007/s11888-020-00456-1 32607098 PMC7325521 Park R, Umar S, Kasi A. Immunotherapy in Colorectal Cancer: Potential of Fecal Transplant and Microbiota-Augmented Clinical Trials. Curr Colorectal Cancer Rep. 2020. 10.1007/s11888-020-00456-1 32607098 10.1007/s11888-020-00456-1 PMC7325521

234. Chrysostomou D Roberts LA Marchesi JR Kinross JM Gut microbiota modulation of efficacy and toxicity of cancer chemotherapy and immunotherapy Gastroenterology 2023 10.1053/j.gastro.2022.10.018 36309208 Chrysostomou D, Roberts LA, Marchesi JR, Kinross JM. Gut Microbiota Modulation of Efficacy and Toxicity of Cancer Chemotherapy and Immunotherapy. Gastroenterology. 2023 10.1053/j.gastro.2022.10.018 36309208 10.1053/j.gastro.2022.10.018

235. Martyniak A Medyńska-Przęczek A Wędrychowicz A Skoczeń S Tomasik PJ Prebiotics, probiotics, synbiotics, paraprobiotics and postbiotic compounds in IBD Biomolecules 2021 10.3390/biom11121903 34944546 PMC8699341 Martyniak A, Medyńska-Przęczek A, Wędrychowicz A, Skoczeń S, Tomasik PJ. Prebiotics, probiotics, synbiotics, paraprobiotics and postbiotic compounds in IBD. Biomolecules. 2021.10.3390/biom11121903 34944546 10.3390/biom11121903 PMC8699341

236. Luo H Shan J Zhang H Song G Li Q Xu CX Targeting the epigenetic processes to enhance antitumor immunity in small cell lung cancer Semin Cancer Biol 2022 10.1016/j.semcancer.2022.02.018 35189321 Luo H, Shan J, Zhang H, Song G, Li Q, Xu CX. Targeting the epigenetic processes to enhance antitumor immunity in small cell lung cancer. Semin Cancer Biol. 2022.10.1016/j.semcancer.2022.02.018 35189321 10.1016/j.semcancer.2022.02.018

237. Connolly RM Rudek MA Piekarz R Entinostat: a promising treatment option for patients with advanced breast cancer Future Oncol 2017 10.2217/fon-2016-0526 28326839 PMC5618943 Connolly RM, Rudek MA, Piekarz R. Entinostat: A promising treatment option for patients with advanced breast cancer. Future Oncology. 2017;13.10.2217/fon-2016-0526 28326839 10.2217/fon-2016-0526 PMC5618943

238. Huang P Wang X Liang X Yang J Zhang C Kong D Nano, micro, and macroscale drug delivery systems for cancer immunotherapy Acta Biomater 2019 10.1016/j.actbio.2018.12.028 30579043 Huang P, Wang X, Liang X, Yang J, Zhang C, Kong D, et al. Nano, micro, and macroscale drug delivery systems for cancer immunotherapy. Acta Biomater. 2019.10.1016/j.actbio.2018.12.028 30579043 10.1016/j.actbio.2018.12.028

239. Sadeghi Rad H, Monkman J, Warkiani ME, Ladwa R, O’Byrne K, Rezaei N, et al. Understanding the tumor microenvironment for effective immunotherapy. Med Res Rev. 2021. 10.1002/med.21765 PMC8247330 33277742

240. Zhao Y Shao Q Peng G Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment Cell Mol Immunol 2020 10.1038/s41423-019-0344-8 31853000 PMC6952436 Zhao Y, Shao Q, Peng G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol Immunol. 2020.10.1038/s41423-019-0344-8 31853000 10.1038/s41423-019-0344-8 PMC6952436

241. Fujiwara Y Kato S Nesline MK Conroy JM DePietro P Pabla S Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy Cancer Treat Rev 2022 10.1016/j.ctrv.2022.102461 36058143 PMC12187009 Fujiwara Y, Kato S, Nesline MK, Conroy JM, DePietro P, Pabla S, et al. Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy. Cancer Treat Rev. 2022.10.1016/j.ctrv.2022.102461 36058143 10.1016/j.ctrv.2022.102461 PMC12187009

242. Ananieva E Targeting amino acid metabolism in cancer growth and anti-tumor immune response World J Biol Chem 2015 10.4331/wjbc.v6.i4.281 26629311 PMC4657121 Ananieva E. Targeting amino acid metabolism in cancer growth and anti-tumor immune response. World J Biol Chem. 2015;6. 10.4331/wjbc.v6.i4.281 26629311 10.4331/wjbc.v6.i4.281 PMC4657121

243. Karimi S, Bakhshali R, Bolandi S, Zahed Z, Mojtaba Zadeh SS, Kaveh Zenjanab M, et al. For and against tumor microenvironment: nanoparticle-based strategies for active cancer therapy. Mater Today, Bio [Internet]. 2025;31:101626. Available from: https://www.sciencedirect.com/science/article/pii/S259000642500184X 10.1016/j.mtbio.2025.101626 PMC11926801 40124335

244. Liu YT Sun ZJ Turning cold tumors into hot tumors by improving T-cell infiltration Theranostics 2021 10.7150/thno.58390 33859752 PMC8039952 Liu YT, Sun ZJ. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics. 2021.10.7150/thno.58390 33859752 10.7150/thno.58390 PMC8039952

245. O’Byrne KJ Lee KH Kim SW Park K Nishio M Sakai H First-line nivolumab + ipilimumab in advanced NSCLC: checkmate 227 subpopulation analyses in Asian patients ESMO Open 2022 10.1016/j.esmoop.2022.100394 35158207 PMC8864530 O’Byrne KJ, Lee KH, Kim SW, Park K, Nishio M, Sakai H, et al. First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. ESMO Open. 2022;7. 10.1016/j.esmoop.2022.100394 35158207 10.1016/j.esmoop.2022.100394 PMC8864530

246. Chesney JA Ribas A Long GV Kirkwood JM Dummer R Puzanov I Randomized, double-blind, placebo-controlled, global phase III trial of Talimogene Laherparepvec combined with pembrolizumab for advanced melanoma J Clin Oncol 2023 10.1200/JCO.22.00343 35998300 PMC9870217 Chesney JA, Ribas A, Long G V., Kirkwood JM, Dummer R, Puzanov I, et al. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined with Pembrolizumab for Advanced Melanoma. Journal of Clinical Oncology. 2023;41.10.1200/JCO.22.00343 35998300 10.1200/JCO.22.00343 PMC9870217

247. Huh WK Brady WE Fracasso PM Dizon DS Powell MA Monk BJ Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: an NRG oncology/gynecologic oncology group study Gynecol Oncol 2020 10.1016/j.ygyno.2020.06.493 32641240 PMC7487015 Huh WK, Brady WE, Fracasso PM, Dizon DS, Powell MA, Monk BJ, et al. Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: An NRG oncology/gynecologic oncology group study. Gynecol Oncol. 2020;158.10.1016/j.ygyno.2020.06.493 32641240 10.1016/j.ygyno.2020.06.493 PMC7487015

248. Neelapu SS, Jacobson CA, Ghobadi A, Miklos DB, Lekakis LJ, Oluwole OO, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. 2023;141. 10.1182/blood.2022018893 PMC10646788 36821768

249. Bauman J, Burris H, Clarke J, Patel M, Cho D, Gutierrez M, et al. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. 2020.

250. Packiam VT Lamm DL Barocas DA Trainer A Fand B Davis RL An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: interim results Urol Oncol Semin Orig Investig 2018 10.1016/j.urolonc.2017.07.005 28755959 Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: Interim results. Urologic Oncology: Seminars and Original Investigations. 2018;36.10.1016/j.urolonc.2017.07.005 10.1016/j.urolonc.2017.07.005 28755959

251. Kantarjian H Stein A Gökbuget N Fielding AK Schuh AC Ribera J-M Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia N Engl J Med 2017 10.1056/NEJMoa1609783 28249141 PMC5881572 Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: Interim results. Urologic Oncology: Seminars and Original Investigations. 2018;36.10.1056/NEJMoa1609783 28755959 10.1016/j.urolonc.2017.07.005

252. Nooka AK, Wang ML, Yee AJ, Kaufman JL, Bae J, Peterkin D, et al. Assessment of safety and immunogenicity of PVX-410 vaccine with or without lenalidomide in patients with smoldering multiple myeloma: a nonrandomized clinical trial. JAMA Oncol. 2018;4. 10.1001/jamaoncol.2018.3267 PMC6440721 30128502

253. Sanoff HK Moon DH Moore DT Boles J Bui C Blackstock W Phase I/II trial of nanocamptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer Nanomedicine 2019 10.1016/j.nano.2019.02.021 30858085 PMC7881832 Sanoff HK, Moon DH, Moore DT, Boles J, Bui C, Blackstock W, et al. Phase I/II trial of nanocamptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer. Nanomedicine. 2019;18.10.1016/j.nano.2019.02.021 30858085 10.1016/j.nano.2019.02.021 PMC7881832

254. Wang J, Baidoun F, Tun HW, Alhaj Moustafa M. 90Yttrium Ibritumomab Tiuxetan (Zevalin) for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: a report of 5 cases. Blood Lymphat Cancer. 2023;13. 10.2147/BLCTT.S398809 PMC10559791 37810176

255. Piña-Sánchez P Chávez-González A Ruiz-Tachiquín M Vadillo E Monroy-García A Montesinos JJ Cancer biology, epidemiology, and treatment in the 21st century: current status and future challenges from a biomedical perspective Cancer Control 2021 10.1177/10732748211038735 34565215 PMC8481752 Piña-Sánchez P, Chávez-González A, Ruiz-Tachiquín M, Vadillo E, Monroy-García A, Montesinos JJ, et al. Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective. Cancer Control. 2021. 10.1177/10732748211038735 34565215 10.1177/10732748211038735 PMC8481752

256. Tormoen GW Crittenden MR Gough MJ Role of the immunosuppressive microenvironment in immunotherapy Adv Radiat Oncol 2018 10.1016/j.adro.2018.08.018 30370351 PMC6200899 Tormoen GW, Crittenden MR, Gough MJ. Role of the immunosuppressive microenvironment in immunotherapy. Adv Radiat Oncol. 2018.10.1016/j.adro.2018.08.018 30370351 10.1016/j.adro.2018.08.018 PMC6200899

257. Li Y Xiang S Pan W Wang J Zhan H Liu S Targeting tumor immunosuppressive microenvironment for pancreatic cancer immunotherapy: current research and future perspective Front Oncol 2023 10.3389/fonc.2023.1166860 37064113 PMC10090519 Li Y, Xiang S, Pan W, Wang J, Zhan H, Liu S. Targeting tumor immunosuppressive microenvironment for pancreatic cancer immunotherapy: Current research and future perspective. Front Oncol. 2023.10.3389/fonc.2023.1166860 37064113 10.3389/fonc.2023.1166860 PMC10090519

258. Choi J Lee SY Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors Immune Netw 2020 10.4110/in.2020.20.e9 32158597 PMC7049586 Choi J, Lee SY. Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors. Immune Netw. 2020.10.4110/in.2020.20.e9 32158597 10.4110/in.2020.20.e9 PMC7049586

259. Liu Z Zhu Y Xie H Zou Z Immune-mediated hepatitis induced by immune checkpoint inhibitors: current updates and future perspectives Front Pharmacol 2023 10.3389/fphar.2022.1077468 36699050 PMC9868416 Liu Z, Zhu Y, Xie H, Zou Z. Immune-mediated hepatitis induced by immune checkpoint inhibitors: Current updates and future perspectives. Front Pharmacol. 2023. 10.3389/fphar.2022.1077468 36699050 10.3389/fphar.2022.1077468 PMC9868416

260. Michel L Rassaf T Totzeck M Cardiotoxicity from immune checkpoint inhibitors IJC Heart Vasc 2019 10.1016/j.ijcha.2019.100420 PMC6736791 31517036 Michel L, Rassaf T, Totzeck M. Cardiotoxicity from immune checkpoint inhibitors. IJC Heart and Vasculature. 2019.10.1016/j.ijcha.2019.100420 10.1016/j.ijcha.2019.100420 PMC6736791 31517036

261. Verma V, Sprave T, Haque W, Simone CB, Chang JY, Welsh JW, et al. A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. J Immunother Cancer. 2018 10.1186/s40425-018-0442-7 PMC6251215 30470252

262. Zhang C, Zhang J, Tan J, Tian P, Li W. Cost-Effectiveness of Pembrolizumab for the treatment of Non–Small-Cell lung cancer: A systematic review. Front Oncol. 2022 10.3389/fonc.2022.815587 PMC9469648 36110966