Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development.

1. Introduction

Cancer remains a major public health challenge globally, with tens of millions diagnosed annually [ 1 ]. In many countries, it ranks as the second leading cause of death following cardiovascular diseases. Moreover, the incidence and mortality of cancer are expected to rise due to population aging and lifestyle changes [ 2 ]. Current cancer treatments encompass immunotherapy, biotherapy, adjuvant chemotherapy, surgery, and diverse drug combinations, including concurrent chemotherapy and radiation therapy or sequential neoadjuvant chemotherapy [ 3 ].

Research indicates that for certain cancers, such as colorectal cancer(CRC), primary treatments like chemotherapy and surgery cannot completely eradicate tumors [ 3 ]. Post-surgery, patients face a continual risk of cancer recurrence, impacting their quality of life [ 4 ]. The adverse effects of chemotherapy, including potential liver damage such as steatohepatitis, steatosis, and sinusitis, can lead to severe outcomes like liver failure [ 5 , 6 ]. Moreover, chemotherapy may harm healthy cells. Over the past fifty years, cancer treatment strategies have evolved from using highly toxic agents like nitrogen mustard to more tolerable targeted therapies [ 7 ]. Nevertheless, challenges such as chemotherapy resistance and recurrence persist, necessitating the exploration of novel therapeutic strategies [ 8 ]. One of the prominent therapeutic approaches today is tumor immunotherapy, which has shown promising therapeutic effects [ 9 ]. Compared to chemotherapy, immunotherapy is associated with fewer cytotoxic side effects [ 10 ] and offers new hope for tumor treatment by targeting specific proteins expressed by cancer cells.

Immunotherapy seeks to enhance immune activity and modulate the immune system to eliminate cancer cells. This innovative approach is proving beneficial for various cancers. This review will detail the advantages and recent clinical progress of tumor immunotherapy, providing a comprehensive summary of new or repurposed drugs based on immunotherapy in recent years. Additionally, it will address immune senescence, a significant factor in tumor development and treatment, discussing its processes, markers, and targeted therapeutic strategies. This aims to surpass the current limitations of tumor immunotherapy and unlock new therapeutic possibilities for cancer patients.

2. Immunotherapy: Booming in Tumor Treatment

The immune system plays a pivotal role in detecting cancer and halting its progression [ 11 ]. To fully understand the central role of immunotherapy in cancer treatment, it is essential to comprehend the interactions between the immune system and cancer cells comprehensively. The immune system, a complex network of cells, distinguishes between self and non-self, thus protecting the body against both endogenous and exogenous diseases. It also regulates other bodily systems, including the inflammatory response, coagulation mechanisms, and immune surveillance. The immune system comprises white blood cells, lymphoid tissues, and organs such as the bone marrow, lymphatic vessels, lymph nodes, tonsils, spleen, and thymus, effectively recognizing and eliminating a broad spectrum of threats to maintain homeostasis. These functions extend to regulating fluid balance, eradicating harmful microorganisms, and suppressing or destroying cancer cells [ 12 , 13 ]. Unlike chemotherapy, which destroys cancer cells through cytotoxic activities, immunotherapy activates the host’s immune response, enhancing the immune cells’ ability to identify and eliminate tumor cells. This strategy has not only transformed the treatment of certain cancers but has also emerged as a favored strategy in recent years, clinically verified to be effective against a wide range of malignant tumors [ 14 , 15 ].

2.1. Definition and Classification of Immunotherapy

Immunotherapy is a method of enhancing or rebuilding the immune system through the use of specific substances to prevent and combat disease. This therapy targets tumors by introducing drugs or agents that stimulate the immune system to generate an immune response. The objective is to optimize the immune system’s function to eradicate cancer cells and augment immune activity, while avoiding an uncontrolled autoimmune inflammatory response that could compromise treatment effectiveness [ 16 ].

Immunotherapy includes a diverse array of therapies based on antibodies and T-cell transfer, such as monoclonal antibodies, oncolytic viral therapies, cancer vaccines, cytokine drugs, checkpoint inhibitors, and chimeric antigen receptor (CAR) T-cell therapies, classified by their mechanism of action. Generally, immunotherapy is divided into two types: passive and active. Active immunotherapies, like oncolytic vaccines, are capable of inducing direct, lasting immune-memory responses. In contrast, passive immunotherapies, such as monoclonal antibodies, elicit a targeted response that is typically transient, necessitating frequent administration [ 17 ]. Response to immunotherapy, at both radiologic and clinical levels, can be variable, often due to the extended time needed for T cells to mount an immune response and eliminate the tumor. The enduring immune-memory characteristic of immunotherapy offers several benefits, including prolonged immune effects post-treatment, potentially leading to continued anti-tumor activity and enhanced long-term survival. Despite chemotherapy’s effectiveness in killing cancer cells, residual immune deficiencies may increase the risk of recurrence. Immunotherapy addresses this risk by boosting resistance [ 17 ].

2.2. Dynamics of T Cells in Immunotherapy

T cells, as fundamental components of the immune system, are crucial for the effective recognition and elimination of tumor cells through immunotherapy. A reduction in T cells not only impedes the primary function of immune checkpoint inhibitors but also impacts the resistance pathways of cellular immunotherapy, thereby diminishing the clinical efficacy of immunotherapy and patient quality of life [ 18 , 19 ]. Thus, comprehending the dynamics of T cells during cancer progression is essential for advancing immunotherapeutic strategies. T-cell depletion is a differentiation process triggered by chronic antigen exposure, leading to the continuous stimulation of the T-cell receptor (TCR) and downstream Ca 2+ signaling, which activates the transcription factor nuclear factor of activated T-cells (NFAT). This activation of NFAT enhances the expression of various inhibitory immune checkpoint proteins (including PD-1, CTLA4, and CD39), resulting in a progressive decrease in T cell effector function and a diminished anti-tumor capacity of the body [ 20 ]. The spectrum of T-cell depletion ranges from highly proliferative T-cells with stem cell-like properties (referred to as “precursor-depleted T-cells”) to T-cells that have entirely lost their effector functions and replicative abilities (often termed “terminally depleted T-cells”). The depletion of T cells leads to a reduced expression of co-stimulatory markers and diminished production of inflammatory cytokines (e.g., IFNγ and TNF), further weakening the body’s anti-tumor capacity [ 21 , 22 ]. Overall, the extent of T-cell exhaustion is gauged by the expression of PD-1 on intratumoral lymphocytes, which is strongly associated with cancer patient survival. Exploring factors that influence T-cell status opens new avenues for the enhancement of cancer immunotherapy [ 23 , 24 , 25 , 26 , 27 ].

2.3. Advantages of Immunotherapy

In oncology, the advancement of immunotherapy and precision medicine is flourishing. Over the past 15 years, the emergence and ascent of cancer immunotherapy have not only transformed clinical oncology practices but have also significantly enhanced our understanding of cancer’s biological mechanisms [ 28 ]. Today, immunotherapeutic agents are indispensable in cancer treatment, offering new options for an expanding patient population. Cancer affects a vast number of people globally, and sustained, detailed research in oncology has greatly advanced our knowledge of cancer and the immune system. A range of clinically validated immunotherapies has altered traditional treatment paradigms and revolutionized tumor immunology. Effective treatments, such as adoptive T-cell therapy (ACT) and immune checkpoints inhibitors (ICIs), are now routinely used in clinics, providing new hope, particularly for patients unresponsive to chemotherapy. These therapies are acknowledged as vital in extending the lives of many patients [ 29 , 30 , 31 ]. Intensive ongoing research aims to further improve the efficacy of immunotherapy in cancer management. Advances in technology have deepened our understanding of the molecular dynamics of various malignancies and their interaction with the human immune system, leading to innovative therapeutic approaches. Some of these approaches have converted previously lethal cancers into manageable or even curable conditions. Recent immunotherapy research has concentrated on identifying tumor antigens to bolster clinical anti-tumor immunity. Several immunotherapies have been officially sanctioned for cancer treatment.

3. Immunotherapy via Diverse Mechanisms

3.1. ICIs Based on Various Targets

Effective anti-tumor responses necessitate moderate T cell activation, which depends on two crucial signals: the antigen-specific signals mediated by the TCR and costimulatory signals from a combination of stimulatory and inhibitory receptors [ 32 ]. Immune checkpoints (ICs), key regulators in T cell activation and tolerance, modulate the immune response through co-inhibitory or co-stimulatory signals [ 33 ], helping to limit host damage, and are vital for maintaining immune homeostasis and self-tolerance. However, prolonged exposure to neoantigens and continuous T-cell stimulation can lead to an increased expression of immune checkpoints, eventually causing T-cell exhaustion. This mechanism, mediated by immune checkpoints, promotes tumor immune escape. Currently, immunotherapeutic strategies targeting these checkpoints focus on blocking co-suppressive T cell signaling to reinvigorate effective anti-tumor immune responses. The inhibitors targeting these checkpoints are monoclonal antibodies designed to treat tumors and are referred to as immune checkpoint inhibitors [ 34 ]. Over twenty monoclonal antibodies targeting PD-1, PD-L1, CTLA-4, and LAG-3 are now approved for treating various types of cancer, including the latest market entries and some repurposed older drugs ( Table 1 ).

3.1.1. Targets PD-1 and PD-L1

When T cells involved in the tumor response are activated, PD-1 expression is upregulated. This upregulated PD-1 binds to its ligands, PD-L1 or PD-L2, which are abundantly expressed on the surfaces of tumor cells, thereby impairing antigen presentation to T cells and interrupting the antigen presentation phase of the tumor immune process ( Figure 1 ). The interaction of PD-1 with its ligands, PD-L1 and PD-L2, on tumor-infiltrating lymphocytes (TILs) is widely regarded as a critical mechanism for tumor immune evasion, making it a crucial therapeutic target. Unlike typical ligand-receptor interactions, which are unidirectional, PD-L1, the primary ligand for PD-1, can also receive inhibitory signals from PD-1, demonstrating a complex regulatory mechanism in T cell signaling along the PD-1 axis [ 35 , 36 ].

Additionally, a range of drugs targeting PD-1 and PD-L1, including Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Durvalumab, and Atezolizumab, have been approved for treating recurrent head and neck squamous cell carcinoma, CRC, NMIBC, endometrial cancer, and various other solid tumors.

3.1.2. Target CTLA-4

During T cell activation and proliferation, CTLA-4 and CD28 of the B7 family of receptors assume negative and positive roles, respectively, in the initial phases of the immune response [ 37 ]. Within the lymph node, CTLA-4 on the surface of T cells supplants the stimulatory receptor CD28 and binds to the ligands CD80 and CD86 [ 38 , 39 , 40 , 41 ], a process that leads to a reduced reactivity of antigen-presenting cells (typically denatured cells), thereby preventing further T cell activation [ 39 , 41 ] ( Figure 1 ). Consequently, by blocking CTLA-4 at an early stage of the T cell maturation process, we aim to enhance the anti-tumor immune response [ 42 ].

3.1.3. Co-stimulation or Co-inhibition of Other Immune Checkpoints

In addition to well-known ICs like PD-1 and CTLA-4, numerous preclinical and clinical studies are targeting T-cell co-suppressor or co-activator molecules. Most of these molecules display detrimental immunomodulatory effects in cancer contexts, while those with beneficial immunomodulatory impacts are being explored for cancer immunotherapy applications [ 43 ].

Interactions between lymphocyte activation gene-3 (LAG-3 or CD223), T-cell immunoglobulin, and mucin domain-containing-3 (TIM-3), and their various ligands (e.g., Galectin-9, HMGB1, PS, and CD66a) diminish anti-tumor immunity through mechanisms such as inducing CD8 + T cell death and exhaustion [ 44 , 45 ]. Research has shown that LAG-3 not only inhibits CD8 + T cell function but also bolsters the immunosuppressive capabilities of regulatory T cells (Tregs) [ 46 ]. In March 2022, the FDA approved Relatlimab, a human lgG4-type LAG-3 monoclonal antibody developed by Bristol-Myers Squibb, for treating unresectable or metastatic melanoma in combination with the anti-PD-1 antibody Nivolumab [ 47 ]. This approval highlights LAG-3’s potential as a promising tumor immunotherapy target, succeeding PD-1 and CTLA-4. Other ICs like T-cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), interacting with ligands such as CD155 and CD112, VSIG-3, exhibit immunosuppressive effects, and inhibitors targeting these have shown significant clinical promise [ 48 , 49 ]. Additional inhibitory checkpoint molecules under investigation include sialic acid-binding Ig-like lectin 15 (Siglec-15) ( NCT03665285 ), B and T lymphocyte attenuator (BTLA or CD272) ( NCT04137900 ), and B7-H3 (CD276) ( NCT02628535 , NCT03406949 ).

Conversely, co-stimulatory molecules like inducible T cell co-stimulator (ICOS), glucocorticoid-induced TNFR-related protein (GITR), and OX40, expressed on various immune (e.g., T cells, Tregs, and NK cells) and non-immune cells (e.g., endothelial cells), are being evaluated for their potential in cancer immunotherapy. These molecules not only enhance the functionality of immune cells such as CD8 + T cells and Tregs but also regulate helper T cell responses by reducing T cell apoptosis [ 50 , 51 ]. Currently, trials involving ICOS agonist monoclonal antibodies, both as standalone therapies and in combination with anti-PD-1 or anti-CTLA-4 therapies, are underway.

3.1.4. Double Immunotherapy

Despite unprecedented advances in cancer treatment with ICI, the proportion of patients deriving clinical benefits remains limited [ 43 ]. To address the shortcomings of individual ICI therapies, researchers are utilizing established and emerging diagnostic strategies, such as genetic and immune biomarkers, to more precisely predict treatment efficacy and to counteract drug resistance through combination therapies.

Compared to monotherapy, combination therapy presents several advantages: it acts on multiple pathways simultaneously, induces synergistic effects, circumvents dosage constraints, and mitigates drug resistance.

3.2. Adoptive Cell Therapy (ACT)

ACT involves harvesting immune cells from a patient’s body, culturing and expanding them in vitro, enhancing their targeted killing function, and then reinfusing these modified cells back into the patient. This process aims to eliminate pathogens, cancerous cells, and mutated cells from the blood and tissues. Currently, therapies that enhance natural anti-tumor activity (such as immune checkpoint blockade) and those that administer specific anti-tumor immune cells (overt T-cell therapy ACT) have received extensive clinical validation and approval. Although both approaches aim to stimulate specific anti-tumor responses in T cells, the efficacy of ICIs is limited by the patient’s own immune tumor-reactive T cell population and may be less effective against less immunogenic cancers. In contrast, ACT, by administering tumor-specific T cells, can recognize these poorly immunogenic cancer types and has the potential to enhance the therapeutic efficacy of ICIs [ 52 ]. Among ACT therapies, the more researched therapies are CAR-T, CAR-NK, TCR-T, and TILs therapies, which differ in terms of cell source, principle of action, durability and infiltration capacity ( Table 2 ). Over a dozen ACT drugs have been approved for marketing in China, and recent significant breakthroughs have been made in the U.S. in drug studies on TILs, TCR-T, and CAR-T ( Table 3 ).

3.2.1. TILs

TILs are isolated from surgically resected tumor samples and expanded in vitro before being infused into lymphocytopenic patients ( Figure 2 ). The use of interleukin-2 (IL-2), a T-cell growth factor, has enabled large-scale in vitro expansion of TILs and demonstrated increased lethality against tumor cells in conditions such as melanoma, HCC, lung carcinoma, ovarian cancer, and other solid tumors [ 53 ]. In February 2024, the FDA approved a global TIL cell product called lifileucel for the treatment of adult patients with unresectable or metastatic melanoma who have previously received PD-1 antibody therapy. This approval marks the first commercially available TIL therapeutic and represents a significant advancement in the treatment of solid tumors. If the tumor is BRAFV600-positive, treatment may include a BRAF inhibitor, with or without an MEK inhibitor. This approval was based on the Phase II C-144-01 study, where lifileucel showed clinically meaningful activity in heavily pretreated patients with advanced melanoma and a high tumor burden [ 54 ]. Iovance Biotherapeutics sponsored a clinical trial that led to lifileucel’s approval. The FDA approved lifileucel dose was administered to over 70 participants, and nearly one-third showed at least some reduction in size, with many tumors disappearing completely. A long-term follow-up study indicated that lifileucel achieved an ORR of 31.4%, compared to 31.3% for anti-PD-1/PD-L1 therapy in primary refractory patients based on the study criteria [ 54 ].

3.2.2. T-Cell Receptor Chimeric T-Cell Therapy (TCR-T)

Also known as TCR engineered T-cell therapy, TCR-T involves screening for suitable tumor-specific antigens and highly specific TCRαβ chain sequences. These target TCR sequences are then introduced into T cells, where the imported TCRα and β chains dimerize and complex with endogenous CD3 components [ 55 , 56 ]. Typically, these sequences are cloned into retroviral or lentiviral vectors for the in vitro transduction of patient peripheral blood T cells, producing TCR-T cells that specifically recognize tumor antigens [ 57 ] ( Figure 2 ). These cells are then expanded and re-infused into the patient’s body to specifically eliminate tumor cells.

In 2022, the first TCR-T cell therapy product, “Tebentafusp (tebentafusp-tebn/Kimmtrak)”, was approved by the FDA for the treatment of uveal melanoma. This marked the first bispecific T-cell engager (TCE) to be successfully approved. The Phase III clinical study of Tebentafusp enrolled 378 patients with metastatic uveal melanoma and demonstrated that the Tebentafusp group achieved a significant improvement in OS compared to other treatment groups (including Dacarbazine, Ipilimumab, or Pembrolizumab), with a one-year survival rate of 73 percent in the Tebentafusp group versus 58 percent in the comparison groups [ 58 ]. While monotherapy with TCEs has shown significant results in the treatment of hematologic cancers, it has underperformed in the treatment of solid tumors. However, the approval of Tebentafusp confirms the efficacy of TCEs in combating solid tumors, which is of great significance [ 54 ].

3.2.3. Cell Therapy Based on CAR Technology

CAR technology features a switch molecule composed of a specific antigen-binding scFv and a paired cognate leucine zipper. This arrangement includes a universal receptor linked to intracellular signaling domains ( Figure 2 ). In the field of CAR therapies, the development extends beyond T cells to include other immune cells such as CAR-NK, CAR-macrophage (CAR-M), CAR-γδT, and CAR-NKT, which have also garnered extensive attention.

As the pioneering CAR therapy, CAR-T merges the specific binding capabilities of the extracellular single-chain variable region of immunoglobulins with the activation potential of the intracellular region of the TCR to create an artificial chimeric antigen receptor (CAR). This CAR is then transduced into autologous cytotoxic T-lymphocytes to form CAR-T cells [ 59 , 60 ]. Unlike TCRs, which recognize only HLA-restricted antigens and depend on co-stimulatory factors such as CD3, CD4, and CD8 for T-cell activation, CAR-T can identify both cell surface and extended antigens. Since 2017, the FDA has approved five CAR-T products for treating hematologic tumors. However, the use of CAR-T in solid cancer treatment remains limited due to the TME and immunosuppression, with only two CAR-T therapies, Yescarta and Kymriah, approved for lymphoma treatment [ 61 ]. Notably, CAR-T treatments are associated with severe side effects, including cytokine release syndrome and neurotoxicity. To overcome these issues, researchers have developed various strategies, including optimizing CAR constructs and exploring innovative therapeutic combinations to enhance the specificity, infiltration, and efficacy of CAR-T cell therapy [ 62 ].

From 2023 to early March 2024, three CAR-T therapy products were launched in China: fully human targeted BCMA CAR-T Igibiorense injection, CNCT19 cell injection, and Zevor-cel. These products are approved for treating relapsed or refractory multiple myeloma (r/r MM), adult relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), and relapsed or refractory multiple myeloma. Before this, six CAR-T therapies had received FDA approval, including Novartis’ Kymriah (for ALL and DLBCL), Gilead/Kite’s Yescarta (for DLBCL) and Tecartus (for MCL), and Bristol-Myers Squibb’s Breyanzi (for DLBCL) and Abecma (for r/r MM).

CAR-NK therapy is distinguished by its strong anti-tumor activity, high safety profile, diverse sources, and multiple targets [ 63 ]. Its cytotoxicity is comparable to that of CD8-positive cells, with the ability to release both perforin and granzyme. Compared to T-cell therapy, NK cells present a lower risk of inducing graft-versus-host disease (GVHD), making CAR-NK therapy more tolerable for patients undergoing adjuvant therapies such as cytotoxic chemotherapy, radiotherapy, and molecularly targeted therapies [ 64 ]. CAR-M therapy offers several advantages including high intra-tumor migratory capacity, both antigen-dependent and -independent phagocytosis, enhanced antigen presentation, and the remodeling of the immunosuppressive microenvironment. Macrophages contribute to tumor cell elimination through phagocytosis, and the release of reactive oxygen species and nitrogen (ROS/iNOS), while degrading almost all components of the ECM [ 65 , 66 ]. The unique phagocytosis properties of CAR-M therapies may offer greater benefits in the treatment of solid tumors compared to CAR-T and CAR-NK cell therapies. CAR-γδT and CAR-NKT cell therapies exert their effects through various mechanisms, including CAR-mediated killing, antibody-dependent cellular cytotoxicity (ADCC), Fas/FasL, TRAIL, and TNFR pathways. These therapies kill tumor cells and secrete cytokines to activate other immune cells, demonstrating strong anti-tumor activity with minimal immunosuppressive effects [ 67 ]. In recent years, a number of ongoing clinical trials of ACT therapies ( Table 4 ) have highlighted the significant potential and promising future of immune cell therapy as an effective treatment option for patients.

3.3. Cytokine Therapy

Cytokines play a crucial role as mediators in the TME, with cytokines involved in adaptive immune responses (e.g., IFNγ, IL-2, IL-12, and TNF) positively impacting anti-tumor immunity.

IL-2 stimulates T-cell responses, natural killer cell proliferation, CD4 + T-cell activation, and B-cell antibody production. It is currently approved by the FDA for treating patients with RCC and melanoma in stable stages [ 68 ]. High doses of IL-2 have induced anti-tumor immune responses in select cancer patients. Moreover, when combined with the immune checkpoint blocker nivolumab, IL-2 significantly inhibits tumor growth in cancers such as melanoma, RCC, NSCLC, uroepithelial carcinoma, and triple-negative breast cancer (TNBC) [ 69 ].

IL-12 promotes NK and T cell proliferation and cytotoxicity, enhances T1 cell differentiation, and stimulates IFNγ production [ 70 ]. Challenges related to its transient half-life and toxicity can be mitigated through the targeted or localized delivery of IL-12 [ 71 ].

IFNγ induces anti-tumor responses through CD4 + T helper cells and CD8 + T cells. Research has shown that IFNγ enhances immunosuppressive molecule regulation, tumor MHC expression, and T cell infiltration. Currently, combination therapies involving recombinant IFNγ and immune checkpoint inhibitors like pembrolizumab and nivolumab are under development [ 72 ].

Tumor necrosis factor (TNF) promotes tumor activity through various pathways, including cytokine cascade stimulation, fibrotic response induction, and the alteration of adhesion receptors. Studies have shown significant effects of antibody therapies targeting TNF or using soluble TNF receptor fusion protein traps in treating solid tumors [ 73 , 74 ]. Additionally, therapeutic strategies targeting cytokines such as IL-7, IL-15, IL-10, IL-6, and TGF-β have demonstrated promising results in solid tumor clinical trials.

3.4. Cancer Vaccines

Cancer vaccines elicit a strong anti-tumor cytotoxic T-cell response by exposing the immune system to tumor-associated antigens (TAA) or tumor-specific antigens (TSA), which recognize and destroy cancer cells. The first and second HPV vaccines were approved by the FDA in 2006 and 2010, respectively. In 2010, Sipuleucel-T (Provenge, Previx), an autologous dendritic cell (DC)-based prostate cancer vaccine, was recognized by the FDA as the first approved therapeutic in tumor vaccines [ 74 , 75 ]. Depending on their preparation, cancer vaccines can be categorized as cellular, peptide, viral, or gene vaccines.

There are two types of cellular vaccines: autologous or genetically modified tumor cells and activated DC vaccines. Tumor cell vaccines contain a complete complement of TAA, including epitopes for CD4 + T cells and CTLs. DCs activate naïve T cells to stimulate an immune response and collaborate with other immune cells. The development of anti-TME vaccines involves preparing DCs in large quantities and loading them with various TAAs or adjuvants to enhance the immune response against tumors [ 76 ].

Viral vaccines are the most effective method for inducing cellular and, to a lesser extent, humoral immune responses [ 77 ]. In 2015, the FDA authorized T-VEC for the treatment of melanoma, marking it as the first FDA-approved oncolytic viral-based therapy. This therapy regulates both local and systemic immune responses against tumors through the direct lysis of cancer cells and “vaccine-in-place” effects.

Peptide vaccines are designed to identify peptides in pathogens that trigger an immune response, integral to producing the vaccine material. One type of anticancer vaccine derived from peptides is the synthetic long peptide (SLP), which induces new antigen-reactive CD8 + and CD4 + T cell responses [ 78 ]. In contrast, recombinant overlapping peptides can break self-tolerance and generate superior immunogenicity in CD4 + and CD8 + T cells compared to native proteins.

Genetic vaccines are categorized into DNA vaccines and mRNA vaccines. DNA vaccines are heat stable, easy to store and transport, and facilitate mass production, ensuring affordability [ 79 ]. They can induce both humoral and cellular immunity, are easy to manufacture, and can provoke prolonged immune responses, especially those involving antigen-specific CTLs. The enhancement of DNA vaccine immunogenicity can be achieved through several strategies: improved delivery mechanisms, enhanced DNA stability in vivo, and the concurrent delivery of DNA encoding cytokines. Compared to DNA vaccines, mRNA vaccines, which are translated in the cytoplasm and require only membrane traversal, offer a higher level of safety [ 80 ]. Cancer vaccines such as the hepatitis B vaccine, human papillomavirus vaccine, and prostate cancer vaccine have already been approved and are widely used in clinical settings.

4. A Key Player in Influencing the Development and Treatment of Cancer: Immunosenescence

Although cancer immunotherapies are now considered the cornerstone of cancer treatment, there are notable limitations. First, only a small fraction of patients benefit from these therapies, largely due to the significant constraints posed by immunotherapy-related adverse events (irAEs) [ 43 ]. Moreover, the types of irAEs occurring after checkpoint blockade do not appear to be cancer-specific, suggesting that the etiology of irAEs is a drug-induced loss of immune tolerance unrelated to the tumor itself [ 81 , 82 ]. Second, some tumors initially responsive to immunotherapy may eventually develop resistance. Numerous studies are currently evaluating the effectiveness of treatments to counteract this resistance. Additionally, the high cost of immunotherapy, even in developed countries, poses a substantial economic burden, challenging for both society and most patients [ 83 ]. Furthermore, the effects of immunotherapy are not long-lasting; only about one-third of patients experience enduring benefits, a predicament exacerbated by the diversity of immune types and more daunting than acquired treatment resistance. Even when combined with other therapies, long-lasting effects are achieved in fewer than half of the patients. This limitation underscores the vast challenges facing oncology treatment and highlights the critical need for ongoing exploration and innovation in therapeutic strategies. Clinical studies have indicated that older cancer patients, particularly those over 75, typically experience poorer clinical outcomes compared to younger patients, primarily due to age-related comorbidities, declining immune function, and reduced tolerance to treatment side effects. Age-related immune senescence, especially the decline in T-cell function, may result in lower levels of tumor-infiltrating immune cells (TIICs), which in turn curtails the efficacy of cancer immunotherapy to some extent. To address this bottleneck in tumor immunotherapy, we explore the process of immune senescence and its associated markers, examine how immune senescence impacts cancer progression and tumor immunotherapy, and propose new strategies to rejuvenate senescent T cells and modulate their upstream pathways.

With increasing human life expectancy and a trend toward population ageing, the risk of age-related diseases, including tumors, is rising in the elderly population. Concurrently, there has been an increase in the failure rate of immunotherapy and the rate of relapse after treatment [ 84 , 85 ]. This phenomenon, known as immunosenescence, was first proposed by Roy Walford [ 86 , 87 , 88 , 89 , 90 ]. Research has shown significant differences in anti-tumor immune responses between younger and older patients. For example, Palmer et al. conducted extensive research on the age distribution of 100 different tumors and concluded that the immune system plays a crucial role in tumor development [ 91 ]. Additionally, Vatter et al. performed a phenotypic analysis of breast epithelial cells in 57 women aged 16 to 91 years and found that the accumulation of luminal and progenitor cells may increase the risk of cancerous transformation with age [ 91 ]. The incidence and prevalence of most cancers increase with age as tumor escape mechanisms intensify and immune surveillance diminishes. This rising risk is due to a combination of factors that together influence an individual’s susceptibility to cancer. Among these factors, the continuous accumulation of senescent cells in tissues, coupled with reduced immune cell function and proliferative potential, are key components of immune senescence.

4.1. The Process of Immunosenescence and Related Markers

Immunosenescence is an aging process characterized by immune dysfunction, involving the remodeling of multiple organs and cellular-level changes that significantly impact the immune system. These changes lead to progressive alterations in the innate and adaptive immune systems, increasing the risk of diseases such as tumors and infections, and may result in a diminished response to infections or vaccines in older adults [ 92 ]. Immunosenescence is a dynamic and multifactorial biological process influenced by factors including aging itself, chronic inflammation, and microenvironmental changes ( Figure 3 ).

As the immune system ages, it undergoes adaptive metabolic changes. While the biological specifics of these changes are not fully understood, several characteristic alterations have been observed. These include thymic degeneration, the dysfunction of hematopoietic stem cells (HSCs), imbalance in T- and B-cell naïve/memory ratios, increased inflammation, the accumulation of senescent cells, impaired response to neoantigens, heightened glycolysis, mitochondrial dysfunction, and a rise in the production of ROS, genomic instability, and stress responses [ 93 , 94 ]. These modifications are critical for understanding the mechanisms and impacts of immunosenescence, particularly in the context of age-related diseases. Features of immune senescence are closely linked with increased morbidity and mortality from age-related conditions such as metabolic diseases, neurodegenerative disorders, cardiovascular diseases, autoimmune diseases, and cancers in elderly patients [ 94 ]. To fully grasp immune senescence and associated diseases, it is essential to explore molecular mechanisms, immune cell dynamics, and regulatory signaling. A deeper comprehension of these biological processes is expected to yield novel insights and strategies for the prevention and treatment of these age-related diseases ( Figure 3 ).

During immune senescence, all types of immune cell subsets, especially T cells, undergo substantial changes. These changes are marked by decreased T cell production, abnormal T cell metabolism, and imbalances in T subset ratios due to thymic degeneration [ 91 , 95 ]. Thymic degeneration is critical in shaping the balance of immune cells, particularly T cells [ 96 , 97 , 98 ]. The thymus comprises two distinct tissue types: epithelial tissue devoid of thymopoiesis and non-epithelial perivascular space. With the aging of the thymus, the interstitial epithelial layer increasingly disappears, and the perivascular layer progressively fills the thymus. This transition results in a decrease in naïve T cells, an increase in peripheral memory T cells, and a reduced likelihood of newly generated T cells migrating to peripheral tissues [ 99 , 100 , 101 ].

An important hallmark of immunosenescence is the chronic, low-level “inflammation” throughout the body, characterized by elevated blood inflammatory markers, which is considered a central factor in the aging process [ 92 , 102 ]. This inflammation stems from the accumulation of damaged macromolecules, while chronic tissue damage primarily arises from endogenous cellular debris [ 103 ]. Cellular senescence is at the heart of this inflammatory process. According to Effros RB et al., senescent CD8 + T cells accumulate in vivo during immune senescence [ 104 ]. In these senescent cells, the senescence-associated secretory phenotype (SASP) is manifested through the secretion of numerous soluble factors, including interleukin-1 (IL-1), IL-13, IL-18, IL-6, IL-8, and receptors for TNF. These SASP factors operate in an autocrine manner, creating positive and negative feedback loops and regulating the activity of neighboring cells in a paracrine manner, thereby leading to an inflammatory phenotype and exerting a significant influence on the immune aging process [ 105 , 106 , 107 ]. Crucially, SASP can propagate senescence, as it contains prohormonal factors released in extracellular vesicles [ 108 ], which in turn further propagate SASP [ 109 ]. In the context of cancer, SASP significantly affects tumor progression, potentially promoting or impeding it, depending on the specific composition of the SASP [ 110 ]. Thus, SASP may act as a double-edged sword in cancer therapy, as immune cells rely on it to mediate anti-tumor responses [ 111 , 112 , 113 ], promote “senescence surveillance”, and prevent tumorigenesis [ 114 , 115 ]. However, under chronic conditions and pathological states such as established tumors, SASP components like vascular endothelial growth factor (VEGF), CCL5, and IL-6 may induce adverse effects related to cancer, including drug resistance, cancer progression, and cachexia [ 116 , 117 , 118 , 119 , 120 , 121 ]. Therefore, a deeper understanding of the complex interactions between cellular senescence, pro-inflammatory factors, and aging is critical in deciphering the mechanisms of immune senescence and potentially designing interventions to mitigate the detrimental effects of inflammation and promote healthier aging.

4.2. Immunosenescence and Cancer

Immunosenescence is a critical hallmark of aging, strongly associated with cancer and cellular senescence, often leading to a poor prognosis for patients [ 122 ]. During senescence, the immune system fails to effectively eliminate emerging senescent cells, resulting in their accumulation. This accumulation promotes the SASP and a pro-inflammatory state in tissues, potentially inducing or accelerating tumor pathology, especially in the elderly population [ 110 ]. The elderly are particularly vulnerable to various degenerative and oncological disorders due to the decline in normal cellular functions [ 92 ].

T cells are central to the body’s anti-tumor immunity. Research has highlighted that the immune senescence of CD8 + T cells is a crucial factor in tumorigenesis and development [ 123 ]. Thymic degeneration reduces the number and proportion of naïve CD8 + T cells as we age, impairing immune system functionality [ 124 ]. This not only increases susceptibility to age-related diseases but also heightens cancer risk in the elderly. Age-related changes in immune responses, including the downregulation of interferon (IFN) signaling in CD8 + T cells, have been documented in aged mouse models [ 125 ]. In older individuals, immune system imbalances may promote tumor proliferation and accelerate T cell senescence. Concurrently, there is a significant increase in the number of macrophages associated with tumors alongside Tregs [ 126 , 127 , 128 , 129 ]. Tumor cells activate both the PKA-CREB and P38 signaling pathways via endogenous cyclic AMP production, leading to DNA damage and T cell exhaustion [ 130 , 131 ]. Senescent T cells enhance immune checkpoint receptor expression and increase PD-L1 expression in tumor cells [ 132 , 133 ]. Glucose exposure activates the ATM and AMPK pathways, further accelerating T cell senescence [ 134 ]. Senescent T cells increasingly rely on anaerobic glycolysis for energy, resulting in impaired mitochondrial function and increased ROS production. Additionally, signaling pathways such as cGAS-STING, C/EBPβ, and NFκB are closely linked to T cell senescence [ 94 ]. These findings illustrate a complex interplay between aging, immune senescence, and tumor development, shedding light on the intricate effects of age on cancer progression and prognosis.

As medical science advances, immunotherapy has emerged as a promising tool to rejuvenate the aging immune system in elderly cancer patients. However, implementing this strategy presents a key challenge: the TME, a complex network that directly impacts the efficacy of immune checkpoint blockade therapy and other novel immunotherapies. As cancer progresses, the TME evolves to suppress immune responses, inhibiting immune cells from destroying malignant or tumor cells. Thus, understanding the immune regulation within the TME is crucial. In the TME, cancer-specific antigens produced during tumorigenesis are processed and captured by DCs. These activated DCs migrate to lymph nodes draining the tumor, where they activate and differentiate naive T cells into effector T cells capable of recognizing and eliminating tumor cells. These activated effector T cells then migrate from the lymph node through the vasculature to the tumor, penetrating the tumor bed in a multi-step process that includes adhesion between vascular endothelial cells and T cells, and migration across the endothelium [ 135 , 136 ]. When T cells infiltrate the tumor bed, their recognition of specific tumor antigens enables them to destroy cancer cells, stimulating further antigen secretion and the successive activation of the cancer immune cycle ( Figure 4 ) [ 137 ]. To overcome these challenges, we propose a new strategy—modulating the tumor immune microenvironment. By regulating factors such as cell metabolism, signaling pathways, and immune cell activity within the TME, we aim to enhance the effectiveness of immunotherapy and improve the lifespan and overall quality of life for elderly patients diagnosed with cancer. After extensive clinical trials, several tumor immune microenvironment modulators have demonstrated therapeutic effects. For example, small-molecule PD-1/PD-L1 inhibitors (INCB086550 and IMMH-010), IDO1 inhibitors (LY-3381916 and Indoximod), and TGF-βRI inhibitors (LY-2157299, GW788388 , EW-7197, and LY-3200882) can be used alone or in combination with immune checkpoint-targeting drugs to potentially achieve better efficacy [ 138 , 139 , 140 , 141 ].

Through a comprehensive analysis and precise modulation of the tumor immune microenvironment, we aim to develop a novel and effective immunotherapy pathway for elderly cancer patients. Recently, the pivotal role of immune senescence in tumor progression has garnered significant attention, necessitating a further exploration of the inherent connection between immune system senescence and the efficacy of immunotherapies. This will aid in optimizing immunotherapeutic strategies for elderly cancer patients.

4.3. Impact of Immune Senescence on Tumor Immunotherapy

As the elderly population expands, the significance of immunotherapy for treating older cancer patients increases. Immunotherapy’s effectiveness varies between older and younger patients due to factors such as cancer type, disease stage, and comorbidities. It is critical to thoroughly investigate immunotherapy’s efficacy in this demographic to refine therapeutic strategies and meet the unique challenges posed by aging and cancer. Accordingly, our systematic study specifically examines the efficacy of cancer immunotherapy and its influencing factors in the elderly.

Research indicates that the efficacy of immunotherapy can be predicted by the proportion of senescent T-cells prior to treatment, revealing that immune system aging diminishes the effectiveness of ICI. For instance, in NSCLC, preclinical studies have demonstrated reduced efficacy in aged mouse models compared to younger ones, highlighting substantial age-related variations across different tumor types and physiological conditions [ 142 , 143 , 144 ]. Furthermore, the effectiveness of ICI in elderly TNBC mice is limited, as observed in specific studies. Additionally, alterations in the TME, such as decreased IFN signaling and antigen presentation, have been noted in these patients [ 125 ]. Padron et al. reported that anti-PD-1, anti-CTLA-4, and anti-PD-L1 antibodies were highly effective in young melanoma mouse models [ 145 ]. In contrast, older mice showed poor responses to anti-PD-L1 therapy, although anti-PD-1 and anti-CTLA-4 treatments remained effective. Clinical trials have indicated that elderly patients with RCC, uroepithelial carcinoma, and melanoma experience lower progression-free and OS rates compared to younger patients [ 146 ]. However, older melanoma models showed more favorable outcomes with anti-PD-L1, anti-PD-1, and anti-CTLA-4 therapies. A retrospective study also found that senior patients (≥75 years old) with advanced melanoma had better therapeutic outcomes with anti-PD1 therapy, suggesting that ICI might offer enhanced efficacy and tolerability in this group [ 142 , 147 , 148 , 149 , 150 ].

The low participation of elderly patients in ICI clinical trials has led to a scarcity of data regarding their safety and toxicity, and the effects of ICI antibody therapy on this demographic remain underexplored. Unraveling the mechanisms that drive rapid tumor progression and affect the effectiveness of immunotherapy in elderly patients is both critical and challenging [ 151 ]. Furthermore, to improve the efficacy of cancer immunotherapy and tailor treatments, it is essential to examine the relationship between treatment responses and age, as well as the nuanced differences in the TME. This endeavor is crucial and vital to devising more accurate and effective treatment strategies for patients of all ages [ 146 , 152 ]. Despite numerous challenges and uncertainties in this area, the rapid progress of technology and deepening research provide strong grounds for optimism that these strategies will soon offer new hope to many cancer patients.

4.4. Therapeutic Strategies for Immune Aging

In 1939, a pivotal study discovered that caloric restriction in mice and rats effectively extended their lifespan. This was the first evidence that the aging process is modifiable [ 153 ]. Subsequent research in primates confirmed that a restricted diet not only prolongs lifespan but also slows the progression of age-related diseases [ 154 , 155 , 156 ]. Additionally, reducing the number of senescent cells through genetic and pharmacological methods has been shown to prevent and mitigate various age-related disorders [ 157 , 158 ]. Thus, conducting comprehensive research on these interventions and facilitating their widespread implementation in human studies is crucial.

T-cell senescence is a key factor in aging and immune function, significantly affecting immune system efficacy. Simple anti-aging interventions may not yield the desired therapeutic outcomes and could potentially harm healthy tissues, particularly in the elderly. To rejuvenate the T-cell pool, several strategies are viable: first, directly enhancing the degenerating thymus to restore its T-cell production capacity; second, eliminating and replacing senescent T-cells by enabling them to re-enter the cell cycle through cellular reprogramming or extending telomeres; and third, targeting upstream mechanisms that induce senescence [ 146 ].

The degeneration of the thymus is a significant aspect of aging, impacting T-cell production and reducing the body’s tumor-fighting capacity. Researchers have explored various methods to rejuvenate the structure and function of the aging thymus. For instance, studies have shown that transplanting cells from young thymic epithelium into aged or defective thymuses enhances thymic regeneration and boosts T-cell production, thereby directly ameliorating thymic degeneration [ 159 ]. Similarly, injecting a plasmid vector containing FOXN1-cDNA into the thymus of aged mice has been found to partially restore the thymus size and thymocyte count [ 160 ]. This indicates that therapies targeting the FOXN1 gene could potentially revitalize the anatomical structure and physiological function of the aging thymus. Moreover, IL-7 therapy applied to the thymus in older individuals has successfully rejuvenated T-cell development in the elderly [ 161 ]. It has been reported that in response to the reduced T-cell production resulting from thymic deterioration, intervention through modulating immunomodulatory factors is possible. Specifically, IL-7 fusion proteins—IL-7 bound to the N-terminal extracellular structural domain of CCR9—have shown the ability to rejuvenate thymic structure in the elderly, indicating significant potential for targeted cytokine therapy ( Table 5 ). Additionally, it has been demonstrated that rejuvenating thymic function in the elderly can be achieved by optimizing the thymic stromal microenvironment.

There is an association between short telomeres, age-related diseases, and reduced lifespan in both mice and humans. Activating telomerase can prevent telomere shortening. In a mouse model, extending telomeres reduced DNA damage and signs of aging, thereby prolonging the lifespan of the mice [ 164 ]. Alessio Lanna et al. identified a novel mechanism that extends the lifespan of the immune system: the transfer of telomeres from antigen-presenting cells to receptor T-cells increased the telomeres in the T-cells by an average of about 3000 base pairs, an effect substantially greater than that achieved by telomerase alone [ 165 ]. This telomere transfer protects the recipient T-cells from replicative senescence, providing them with enduring immune memory and stem cell characteristics, which enables these T-cells to deliver long-term protection against severe infections. Cyclohexenol has been found to inhibit telomere contraction and boost telomerase activity and proliferation in CD8 + T cells. However, strategies for telomere lengthening may carry potential risks in the context of cancer, due to the absence of specific mechanisms targeting senescent cells [ 166 ].

By precisely regulating the upstream mechanisms that induce T-cell senescence, we effectively modulated the relevant metabolic pathways, thereby preventing the premature senescence of T-cells and enhancing their immune functions. Treg-mediated senescence regulation strategies show considerable promise. In age-related diseases, the increased proportion of Tregs poses a significant barrier to effective immune responses [ 167 , 168 ]. Studies have shown that Treg-induced T-cell senescence can be effectively inhibited in animal models both in vitro and in vivo by modulating glucose metabolism [ 169 ]. At the mechanistic level, poly-G3 activated TLR8 in Treg cells, which subsequently inhibited glucose uptake, transport, and glycolysis. The activation of TLR8 signaling resulted in decreased expression levels of cyclic adenosine monophosphate and mTORC1-HIF-1 signaling, thus reducing metabolic activity and senescence in neoplastic cells. Recent research reveals that senescent T-cell function can be restored via the MAPK pathway. Consequently, by activating TLR8 or inhibiting MAPK signaling in Tregs, we can reverse T-cell senescence both in vitro and in vivo [ 134 ]. Furthermore, activating AMPK pathways has emerged as an innovative approach to counteract cellular aging and bolster the aging immune system [ 126 , 170 ]. The continued exploration of novel molecular and cellular mechanisms linked to premature senescence and inflammation will provide a solid theoretical basis for developing new therapeutic strategies. With advanced deep learning tools, we can more efficiently screen anti-aging drugs [ 171 ]. Finally, an innovative strategy involves restoring immune function by cryopreserving young, functioning autologous leukocytes and re-infusing these cells later or using them in anti-cancer immunotherapy strategies. This approach offers a novel perspective for combating immune system aging and enhancing its functionality [ 172 ].

Recent studies have shown that pharmacologic interventions exhibit some potential in slowing down the aging phenotype. The findings of metformin, a widely used antidiabetic drug, suggest it may play a role in decelerating the aging process [ 173 ]. A retrospective analysis of diabetic patients treated with metformin indicated an increase in life expectancy compared to non-diabetic patients [ 174 ]. Additionally, beneficial effects on aging have been observed in mouse models. However, these findings were primarily conducted in short-lived mouse models prone to cancer under certain conditions. Subsequent studies observed similar phenomena in longer-lived C57BL/6J mice and genetically inbred mice ( Table 5 ). Alejandro Martin-Montalvo’s recent study demonstrated that adding 0.1% metformin to the diet of male C57BL/6J mice (from week 72 to week 90) increased their average lifespan by 4–6% and improved their health indicators [ 175 , 176 ]. MTOR, a critical protein kinase, plays a role in various signal transduction pathways, including energy status, growth factors, nutrient utilization, and stress response [ 177 ]. Numerous studies have shown that the genetic modulation of mTOR signaling can slow the aging process across a variety of organisms [ 178 , 179 , 180 ]. These signaling regulatory mechanisms, which include mRNA translation, transcription, autophagy, and mitochondrial function, are known to facilitate lifespan extension. Furthermore, the binding of rapamycin to FKBP12 disrupts mTORC1 and inhibits its function, showing promise in slowing or reversing various age-related changes [ 181 , 182 ]. Although rapamycin has been effective in extending lifespan and mitigating major pathological changes in mice through its anti-tumor mechanism and reversing enhanced SASP in senescent cells, studies on the mTORC1 pathway provide the most robust clinical evidence to date, suggesting it as a viable strategy to forestall aging ( Table 5 ) [ 167 , 183 ]. However, it is important to note that the lack of selectivity of rapamycin may lead to serious side effects, including inflammatory responses and potential damage to normal tissues. Thus, a thorough exploration and evaluation of its potential safety issues will be a crucial part of future research and application.

As scientific research advances, we are gaining a more detailed understanding of the underlying molecular mechanisms of aging, which opens new opportunities for anti-aging therapies. The impact of immune senescence on tumor growth and development underscores the need for a further exploration of its specific role in tumor treatment and progression. By modulating the SASP during senescence, we can enhance therapeutic outcomes using combination therapies. For instance, chemotherapy-induced SASP can increase susceptibility to PD-1 inhibitors and chemotherapeutic interventions, thereby inhibiting tumor progression and metastasis. Recent investigations have also highlighted that the aging microenvironment is a significant contributor to age-related declines in immune function, offering new potential targets for restoring the immune system.

5. Conclusions and Future Perspectives

Immunotherapy has experienced rapid growth over the past decade, offering the advantages of relatively durable tolerability, minimal side effects, and a broad spectrum of treatments for solid tumors. Unlike conventional chemotherapy and targeted therapies, it does not depend on the cancer cells’ oncogenicity to specific dynamic pathways, such as KRAS mutations. In recent years, there has been progress in repurposing existing drugs for new indications in solid tumors; for example, in 2022, Durvalumab was approved not only for biliary tract cancer but also in combination with Tremelimumab for unresectable HCC. Additionally, therapies previously at a developmental bottleneck have gained approval for solid tumor treatments, such as the first TCR-T drug, Tebentafusp, developed in 2022 for uveal melanoma, and the first TILs drug, lifileucel, developed in 2024 for unresectable or metastatic melanoma. These advances are expected to significantly contribute to tumor immunotherapy. Despite its status as a leading therapy for cancer treatment, immunotherapy still faces challenges, including a limited therapeutic scope and efficacy, high costs, susceptibility to irAEs, and drug tolerance. As the elderly population grows, immune senescence has become a critical factor limiting its effectiveness, yet the age factor is often underrepresented in preclinical studies. Age-related changes in the TME, such as the accumulation of various immunosuppressive cells, increase tumor resistance and immune evasion. A deeper understanding of the complex interactions between aging, cellular senescence, and the TME is crucial for developing more effective cancer treatment strategies and addressing the unique challenges of age-related changes.

We provide insight into the potential mechanisms and therapeutic targets of immune senescence in malignant tumors by describing the process of immune senescence and related markers. Despite significant progress in basic and clinical studies of senescence, current immunological techniques are insufficient to fully unravel the complexity of the immune system. For instance, the applicability of the six-to-eight-week-old mouse model, primarily used in tumor research, may have limitations in human studies. Discussions continue regarding the alignment of age criteria between humans and mice. Therefore, there is a need to develop more representative living models of aging that reflect changes in immune age and time series dynamics. To address the growing public health challenges posed by malignant tumors, a comprehensive understanding of immune senescence and a detailed examination of the complexity of the human immune system still necessitate the use of advanced immunological techniques and experimental tools. Currently, targeting immunosenescent cells is emerging as a novel intervention strategy for cancer therapy, offering new therapeutic opportunities for patients, and is anticipated to lead to significant breakthroughs in cancer treatment.

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Author Contributions

Conception, writing-original draft preparation, Y.F. and C.H.; writing—review and editing, C.L. and B.S.; supervision, D.W. and P.W. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

References

1. Ibrahim A. El Baldi M. Mohammed S. El Rhazi K. Benazzouz B. Cancer statistics in Yemen: Incidence and mortality, in 2020 BMC Public Health 2024 24 962 10.1186/s12889-024-18207-4 38580993 PMC10996160

2. Wilkes G.M. Targeted Therapy: Attacking Cancer with Molecular and Immunological Targeted Agents Asia Pac. J. Oncol. Nurs. 2018 5 137 155 10.4103/apjon.apjon_79_17 29607374 PMC5863423

3. Wujcik D. Science and mechanism of action of targeted therapies in cancer treatment Semin. Oncol. Nurs. 2014 30 139 146 10.1016/j.soncn.2014.05.002 25085025

4. Tavare A.N. Perry N.J. Benzonana L.L. Takata M. Ma D. Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents Int. J. Cancer 2012 130 1237 1250 10.1002/ijc.26448 21935924

5. Manna P. Dewanjee S. Joardar S. Chakraborty P. Bhattacharya H. Bhanja S. Bhattacharyya C. Bhowmik M. Bhowmick S. Saha A. Carnosic acid attenuates doxorubicin-induced cardiotoxicity by decreasing oxidative stress and its concomitant pathological consequences Food Chem. Toxicol. 2022 166 113205 Erratum in Food Chem. Toxicol. 2023 , 181 , 114099 10.1016/j.fct.2023.114099 35675861

6. Nurgali K. Jagoe R.T. Abalo R. Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae? Front. Pharmacol. 2018 9 245 10.3389/fphar.2018.00245 29623040 PMC5874321

7. Masoud V. Pagès G. Targeted therapies in breast cancer: New challenges to fight against resistance World J. Clin. Oncol. 2017 8 120 134 10.5306/wjco.v8.i2.120 28439493 PMC5385433

8. Luo Y. Sun X. Huang L. Yan J. Yu B.Y. Tian J. Artemisinin-Based Smart Nanomedicines with Self-Supply of Ferrous Ion to Enhance Oxidative Stress for Specific and Efficient Cancer Treatment ACS Appl. Mater. Interfaces 2019 11 29490 29497 10.1021/acsami.9b07390 31355624

9. Ai L.J. Li G.D. Chen G. Sun Z.Q. Zhang J.N. Liu M. Molecular subtyping and the construction of a predictive model of colorectal cancer based on ion channel genes Eur. J. Med. Res. 2024 29 219 10.1186/s40001-024-01819-2 38576045 PMC10993535

10. Shahid K. Khalife M. Dabney R. Phan A.T. Immunotherapy and targeted therapy-the new roadmap in cancer treatment Ann. Transl. Med. 2019 7 595 10.21037/atm.2019.05.58 31807576 PMC6861781

11. Hanahan D. Weinberg R.A. Hallmarks of cancer: The next generation Cell 2011 144 646 674 10.1016/j.cell.2011.02.013 21376230

12. Chen C. Ke J. Zhou X.E. Yi W. Brunzelle J.S. Li J. Yong E.L. Xu H.E. Melcher K. Structural basis for molecular recognition of folic acid by folate receptors Nature 2013 500 486 489 10.1038/nature12327 23851396 PMC5797940

13. Han S. Wu J. Three-dimensional (3D) scaffolds as powerful weapons for tumor immunotherapy Bioact. Mater. 2022 17 300 319 10.1016/j.bioactmat.2022.01.020 35386452 PMC8965033

14. Hamilton P.T. Anholt B.R. Nelson B.H. Tumour immunotherapy: Lessons from predator-prey theory Nat. Rev. Immunol. 2022 22 765 775 10.1038/s41577-022-00719-y 35513493

15. Abbott M. Ustoyev Y. Cancer and the Immune System: The History and Background of Immunotherapy Semin. Oncol. Nurs. 2019 35 150923 10.1016/j.soncn.2019.08.002 31526550

16. Chen D.S. Mellman I. Oncology meets immunology: The cancer-immunity cycle Immunity 2013 39 1 10 10.1016/j.immuni.2013.07.012 23890059

17. Twomey J.D. Zhang B. Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics Aaps j 2021 23 39 10.1208/s12248-021-00574-0 33677681 PMC7937597

18. Chow A. Perica K. Klebanoff C.A. Wolchok J.D. Clinical implications of T cell exhaustion for cancer immunotherapy Nat. Rev. Clin. Oncol. 2022 19 775 790 10.1038/s41571-022-00689-z 36216928 PMC10984554

19. Xiang M. Li H. Zhan Y. Ma D. Gao Q. Fang Y. Functional CRISPR screens in T cells reveal new opportunities for cancer immunotherapies Mol. Cancer 2024 23 73 10.1186/s12943-024-01987-z 38581063 PMC10996278

20. Scott A.C. Dündar F. Zumbo P. Chandran S.S. Klebanoff C.A. Shakiba M. Trivedi P. Menocal L. Appleby H. Camara S. TOX is a critical regulator of tumour-specific T cell differentiation Nature 2019 571 270 274 10.1038/s41586-019-1324-y 31207604 PMC7698992

21. Seo H. Chen J. González-Avalos E. Samaniego-Castruita D. Das A. Wang Y.H. López-Moyado I.F. Georges R.O. Zhang W. Onodera A. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8(+) T cell exhaustion Proc. Natl. Acad. Sci. USA 2019 116 12410 12415 10.1073/pnas.1905675116 31152140 PMC6589758

22. Liu X. Wang Y. Lu H. Li J. Yan X. Xiao M. Hao J. Alekseev A. Khong H. Chen T. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction Nature 2019 567 525 529 10.1038/s41586-019-0979-8 30814730 PMC6507425

23. Park J.H. Rivière I. Gonen M. Wang X. Sénéchal B. Curran K.J. Sauter C. Wang Y. Santomasso B. Mead E. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia N. Engl. J. Med. 2018 378 449 459 10.1056/NEJMoa1709919 29385376 PMC6637939

24. Raje N. Berdeja J. Lin Y. Siegel D. Jagannath S. Madduri D. Liedtke M. Rosenblatt J. Maus M.V. Turka A. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma N. Engl. J. Med. 2019 380 1726 1737 10.1056/NEJMoa1817226 31042825 PMC8202968

25. Berdeja J.G. Madduri D. Usmani S.Z. Jakubowiak A. Agha M. Cohen A.D. Stewart A.K. Hari P. Htut M. Lesokhin A. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study Lancet 2021 398 314 324 10.1016/s0140-6736(21)00933-8 34175021

26. Locke F.L. Miklos D.B. Jacobson C.A. Perales M.A. Kersten M.J. Oluwole O.O. Ghobadi A. Rapoport A.P. McGuirk J. Pagel J.M. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma N. Engl. J. Med. 2022 386 640 654 10.1056/NEJMoa2116133 34891224

27. Kamdar M. Solomon S.R. Arnason J. Johnston P.B. Glass B. Bachanova V. Ibrahimi S. Mielke S. Mutsaers P. Hernandez-Ilizaliturri F. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial Lancet 2022 399 2294 2308 10.1016/s0140-6736(22)00662-6 35717989

28. Dang Q. Li B. Jin B. Ye Z. Lou X. Wang T. Wang Y. Pan X. Hu Q. Li Z. Cancer immunometabolism: Advent, challenges, and perspective Mol. Cancer 2024 23 72 10.1186/s12943-024-01981-5 38581001 PMC10996263

29. Yang L. Ning Q. Tang S.S. Recent Advances and Next Breakthrough in Immunotherapy for Cancer Treatment J. Immunol. Res. 2022 2022 8052212 10.1155/2022/8052212 35340585 PMC8956433

30. Darvishi M. Tosan F. Nakhaei P. Manjili D.A. Kharkouei S.A. Alizadeh A. Ilkhani S. Khalafi F. Zadeh F.A. Shafagh S.G. Recent progress in cancer immunotherapy: Overview of current status and challenges Pathol. Res. Pract. 2023 241 154241 10.1016/j.prp.2022.154241 36543080

31. Tjader N.P. Toland A.E. Immunotherapy for colorectal cancer: Insight from inherited genetics Trends Cancer 2024 10 444 456 10.1016/j.trecan.2024.01.008 38360438 PMC11096082

32. He X. Xu C. Immune checkpoint signaling and cancer immunotherapy Cell Res. 2020 30 660 669 10.1038/s41422-020-0343-4 32467592 PMC7395714

33. Rivoltini L. Carrabba M. Huber V. Castelli C. Novellino L. Dalerba P. Mortarini R. Arancia G. Anichini A. Fais S. Immunity to cancer: Attack and escape in T lymphocyte-tumor cell interaction Immunol. Rev. 2002 188 97 113 10.1034/j.1600-065x.2002.18809.x 12445284

34. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy Nat. Rev. Cancer 2012 12 252 264 10.1038/nrc3239 22437870 PMC4856023

35. Dong H. Strome S.E. Matteson E.L. Moder K.G. Flies D.B. Zhu G. Tamura H. Driscoll C.L. Chen L. Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis J. Clin. Investig. 2003 111 363 370 10.1172/jci16015 12569162 PMC151851

36. Azuma T. Yao S. Zhu G. Flies A.S. Flies S.J. Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells Blood 2008 111 3635 3643 10.1182/blood-2007-11-123141 18223165 PMC2275025

37. Harris N.L. Ronchese F. The role of B7 costimulation in T-cell immunity Immunol. Cell Biol. 1999 77 304 311 10.1046/j.1440-1711.1999.00835.x 10457196

38. Schneider H. Downey J. Smith A. Zinselmeyer B.H. Rush C. Brewer J.M. Wei B. Hogg N. Garside P. Rudd C.E. Reversal of the TCR stop signal by CTLA-4 Science 2006 313 1972 1975 10.1126/science.1131078 16931720

39. Riley J.L. Mao M. Kobayashi S. Biery M. Burchard J. Cavet G. Gregson B.P. June C.H. Linsley P.S. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors Proc. Natl. Acad. Sci. USA 2002 99 11790 11795 10.1073/pnas.162359999 12195015 PMC129347

40. Egen J.G. Allison J.P. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength Immunity 2002 16 23 35 10.1016/s1074-7613(01)00259-x 11825563

41. Parry R.V. Chemnitz J.M. Frauwirth K.A. Lanfranco A.R. Braunstein I. Kobayashi S.V. Linsley P.S. Thompson C.B. Riley J.L. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms Mol. Cell Biol. 2005 25 9543 9553 10.1128/mcb.25.21.9543-9553.2005 16227604 PMC1265804

42. Sansom D.M. CD28, CTLA-4 and their ligands: Who does what and to whom? Immunology 2000 101 169 177 10.1046/j.1365-2567.2000.00121.x 11012769 PMC2327073

43. Morad G. Helmink B.A. Sharma P. Wargo J.A. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade Cell 2022 185 576 10.1016/j.cell.2022.01.008 35120665

44. de Mingo Pulido Á. Gardner A. Hiebler S. Soliman H. Rugo H.S. Krummel M.F. Coussens L.M. Ruffell B. TIM-3 Regulates CD103(+) Dendritic Cell Function and Response to Chemotherapy in Breast Cancer Cancer Cell 2018 33 60 74.e66 10.1016/j.ccell.2017.11.019 29316433 PMC5764109

45. Andreae S. Piras F. Burdin N. Triebel F. Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223) J. Immunol. 2002 168 3874 3880 10.4049/jimmunol.168.8.3874 11937541

46. Yano H. Andrews L.P. Workman C.J. Vignali D.A.A. Intratumoral regulatory T cells: Markers, subsets and their impact on anti-tumor immunity Immunology 2019 157 232 247 10.1111/imm.13067 31087644 PMC6587321

47. Chocarro L. Bocanegra A. Blanco E. Fernández-Rubio L. Arasanz H. Echaide M. Garnica M. Ramos P. Piñeiro-Hermida S. Vera R. Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor Cells 2022 11 2351 10.3390/cells11152351 35954196 PMC9367598

48. Stanietsky N. Simic H. Arapovic J. Toporik A. Levy O. Novik A. Levine Z. Beiman M. Dassa L. Achdout H. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity Proc. Natl. Acad. Sci. USA 2009 106 17858 17863 10.1073/pnas.0903474106 19815499 PMC2764881

49. Liu S. Zhang H. Li M. Hu D. Li C. Ge B. Jin B. Fan Z. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells Cell Death Differ. 2013 20 456 464 10.1038/cdd.2012.141 23154388 PMC3569986

50. Fu T. He Q. Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy Cancer Res. 2011 71 5445 5454 10.1158/0008-5472.Can-11-1138 21708958

51. Gray C.C. Armstead B.E. Chung C.S. Chen Y. Ayala A. VISTA Non-redundantly Regulates Proliferation and CD69low γδ T cell Accumulation in the Intestine in Murine Sepsis J. Leukoc. Biol. 2023 115 1005 1019 10.1093/jleuko/qiad149 38035776 PMC11135620

52. Met Ö. Jensen K.M. Chamberlain C.A. Donia M. Svane I.M. Principles of adoptive T cell therapy in cancer Semin. Immunopathol. 2019 41 49 58 10.1007/s00281-018-0703-z 30187086

53. Yamaguchi Y. Ohshita A. Kawabuchi Y. Ohta K. Shimizu K. Minami K. Hihara J. Miyahara E. Toge T. Adoptive immunotherapy of cancer using activated autologous lymphocytes—Current status and new strategies Hum. Cell 2003 16 183 189 10.1111/j.1749-0774.2003.tb00152.x 15147038

54. Chesney J. Lewis K.D. Kluger H. Hamid O. Whitman E. Thomas S. Wermke M. Cusnir M. Domingo-Musibay E. Phan G.Q. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: Pooled analysis of consecutive cohorts of the C-144-01 study J. Immunother. Cancer 2022 10 e005755 10.1136/jitc-2022-005755 36600653 PMC9748991

55. Shirakashi M. Maruya M. Hirota K. Tsuruyama T. Matsuo T. Watanabe R. Murata K. Tanaka M. Ito H. Yoshifuji H. Effect of Impaired T Cell Receptor Signaling on the Gut Microbiota in a Mouse Model of Systemic Autoimmunity Arthritis Rheumatol. 2022 74 641 653 10.1002/art.42016 34725966

56. Traver M.K. Paul S. Schaefer B.C. T Cell Receptor Activation of NF-κB in Effector T Cells: Visualizing Signaling Events Within and Beyond the Cytoplasmic Domain of the Immunological Synapse Methods Mol. Biol. 2017 1584 101 127 10.1007/978-1-4939-6881-7_8 28255699

57. Zhang P. Zhang G. Wan X. Challenges and new technologies in adoptive cell therapy J. Hematol. Oncol. 2023 16 97 10.1186/s13045-023-01492-8 37596653 PMC10439661

58. Dhillon S. Tebentafusp: First Approval Drugs 2022 82 703 710 10.1007/s40265-022-01704-4 35364798

59. Taheri S. Cytokine Release Syndrome after Chimeric Antigen Receptor Transduced T-Cell Therapy in Cancers: A Systematic Review Saudi J. Kidney Dis. Transpl. 2022 33 795 823 10.4103/1319-2442.390259 38018721

60. Kuwana Y. Asakura Y. Utsunomiya N. Nakanishi M. Arata Y. Itoh S. Nagase F. Kurosawa Y. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions Biochem. Biophys. Res. Commun. 1987 149 960 968 10.1016/0006-291x(87)90502-x 3122749

61. Dwivedi A. Karulkar A. Ghosh S. Rafiq A. Purwar R. Corrigendum: Lymphocytes in Cellular Therapy: Functional Regulation of CAR T Cells Front. Immunol. 2019 10 401 10.3389/fimmu.2019.00401 30906295 PMC6418378

62. Gargett T. Brown M.P. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells Front. Pharmacol. 2014 5 235 10.3389/fphar.2014.00235 25389405 PMC4211380

63. Liu Q. Li J. Zheng H. Yang S. Hua Y. Huang N. Kleeff J. Liao Q. Wu W. Adoptive cellular immunotherapy for solid neoplasms beyond CAR-T Mol. Cancer 2023 22 28 10.1186/s12943-023-01735-9 36750830 PMC9903509

64. Pan K. Farrukh H. Chittepu V. Xu H. Pan C.X. Zhu Z. CAR race to cancer immunotherapy: From CAR T, CAR NK to CAR macrophage therapy J. Exp. Clin. Cancer Res. 2022 41 119 10.1186/s13046-022-02327-z 35361234 PMC8969382

65. Tsai H.C. Pietrobon V. Peng M. Wang S. Zhao L. Marincola F.M. Cai Q. Current strategies employed in the manipulation of gene expression for clinical purposes J. Transl. Med. 2022 20 535 10.1186/s12967-022-03747-3 36401279 PMC9673226

66. Cassetta L. Kitamura T. Macrophage targeting: Opening new possibilities for cancer immunotherapy Immunology 2018 155 285 293 10.1111/imm.12976 29963704 PMC6187207

67. Siegers G.M. Dutta I. Lai R. Postovit L.M. Functional Plasticity of Gamma Delta T Cells and Breast Tumor Targets in Hypoxia Front. Immunol. 2018 9 1367 10.3389/fimmu.2018.01367 29963058 PMC6013583

68. Bommareddy P.K. Wakimoto H. Martuza R.L. Kaufman H.L. Rabkin S.D. Saha D. Oncolytic herpes simplex virus expressing IL-2 controls glioblastoma growth and improves survival J. Immunother. Cancer 2024 12 e008880 10.1136/jitc-2024-008880 38599661 PMC11015300

69. Tannir N.M. Cho D.C. Diab A. Sznol M. Bilen M.A. Balar A.V. Grignani G. Puente E. Tang L. Chien D. Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: Results from the PIVOT-02 study J. Immunother. Cancer 2022 10 e004419 10.1136/jitc-2021-004419 35444058 PMC9021810

70. Tait Wojno E.D. Hunter C.A. Stumhofer J.S. The Immunobiology of the Interleukin-12 Family: Room for Discovery Immunity 2019 50 851 870 10.1016/j.immuni.2019.03.011 30995503 PMC6472917

71. Fallon J. Tighe R. Kradjian G. Guzman W. Bernhardt A. Neuteboom B. Lan Y. Sabzevari H. Schlom J. Greiner J.W. The immunocytokine NHS-IL12 as a potential cancer therapeutic Oncotarget 2014 5 1869 1884 10.18632/oncotarget.1853 24681847 PMC4039112

72. Propper D.J. Balkwill F.R. Harnessing cytokines and chemokines for cancer therapy Nat. Rev. Clin. Oncol. 2022 19 237 253 10.1038/s41571-021-00588-9 34997230

73. Perez-Ruiz E. Minute L. Otano I. Alvarez M. Ochoa M.C. Belsue V. de Andrea C. Rodriguez-Ruiz M.E. Perez-Gracia J.L. Marquez-Rodas I. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy Nature 2019 569 428 432 10.1038/s41586-019-1162-y 31043740

74. Rastogi I. Muralidhar A. McNeel D.G. Vaccines as treatments for prostate cancer Nat. Rev. Urol. 2023 20 544 559 10.1038/s41585-023-00739-w 36879114 PMC9987387

75. Xie Y.J. Liu W.Q. Li D. Hou J.C. Coghi P.S. Fan X.X. Overcoming Suppressive Tumor Microenvironment by Vaccines in Solid Tumor Vaccines 2023 11 394 10.3390/vaccines11020394 36851271 PMC9964970

76. Laureano R.S. Sprooten J. Vanmeerbeerk I. Borras D.M. Govaerts J. Naulaerts S. Berneman Z.N. Beuselinck B. Bol K.F. Borst J. Trial watch: Dendritic cell (DC)-based immunotherapy for cancer Oncoimmunology 2022 11 2096363 10.1080/2162402x.2022.2096363 35800158 PMC9255073

77. Anderson R.J. Schneider J. Plasmid DNA and viral vector-based vaccines for the treatment of cancer Vaccine 2007 25 (Suppl. S2) B24 B34 10.1016/j.vaccine.2007.05.030 17698262

78. Sobhani N. Scaggiante B. Morris R. Chai D. Catalano M. Tardiel-Cyril D.R. Neeli P. Roviello G. Mondani G. Li Y. Therapeutic cancer vaccines: From biological mechanisms and engineering to ongoing clinical trials Cancer Treat. Rev. 2022 109 102429 10.1016/j.ctrv.2022.102429 35759856 PMC9217071

79. Duong H.T.T. Thambi T. Yin Y. Kim S.H. Nguyen T.L. Phan V.H.G. Kim J. Jeong J.H. Lee D.S. Degradation-regulated architecture of injectable smart hydrogels enhances humoral immune response and potentiates antitumor activity in human lung carcinoma Biomaterials 2020 230 119599 10.1016/j.biomaterials.2019.119599 31718883

80. Chen Z. Meng C. Mai J. Liu Y. Li H. Shen H. An mRNA vaccine elicits STING-dependent antitumor immune responses Acta Pharm. Sin. B 2023 13 1274 1286 10.1016/j.apsb.2022.11.013 36970194 PMC10031366

81. Boutros C. Tarhini A. Routier E. Lambotte O. Ladurie F.L. Carbonnel F. Izzeddine H. Marabelle A. Champiat S. Berdelou A. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination Nat. Rev. Clin. Oncol. 2016 13 473 486 10.1038/nrclinonc.2016.58 27141885

82. Del Rivero J. Cordes L.M. Klubo-Gwiezdzinska J. Madan R.A. Nieman L.K. Gulley J.L. Endocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management Oncologist 2020 25 290 300 10.1634/theoncologist.2018-0470 32297436 PMC7160393

83. Schaft N. Dörrie J. Schuler G. Schuler-Thurner B. Sallam H. Klein S. Eisenberg G. Frankenburg S. Lotem M. Khatib A. The future of affordable cancer immunotherapy Front. Immunol. 2023 14 1248867 10.3389/fimmu.2023.1248867 37736099 PMC10509759

84. Desdín-Micó G. Soto-Heredero G. Aranda J.F. Oller J. Carrasco E. Gabandé-Rodríguez E. Blanco E.M. Alfranca A. Cussó L. Desco M. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence Science 2020 368 1371 1376 10.1126/science.aax0860 32439659 PMC7616968

85. Fane M. Weeraratna A.T. How the ageing microenvironment influences tumour progression Nat. Rev. Cancer 2020 20 89 106 10.1038/s41568-019-0222-9 31836838 PMC7377404

86. Candeias S.M. Gaipl U.S. The Immune System in Cancer Prevention, Development and Therapy Anticancer. Agents Med. Chem. 2016 16 101 107 10.2174/1871520615666150824153523 26299661

87. Lian J. Yue Y. Yu W. Zhang Y. Immunosenescence: A key player in cancer development J. Hematol. Oncol. 2020 13 151 10.1186/s13045-020-00986-z 33168037 PMC7653700

88. Alizadeh D. Wong R.A. Yang X. Wang D. Pecoraro J.R. Kuo C.F. Aguilar B. Qi Y. Ann D.K. Starr R. IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype Cancer Immunol. Res. 2019 7 759 772 10.1158/2326-6066.Cir-18-0466 30890531 PMC6687561

89. Finn O.J. Immuno-oncology: Understanding the function and dysfunction of the immune system in cancer Ann. Oncol. 2012 23 (Suppl. S8) viii6 viii9 10.1093/annonc/mds256 22918931 PMC4085883

90. Fulop T. Witkowski J.M. Pawelec G. Alan C. Larbi A. On the immunological theory of aging Interdiscip. Top. Gerontol. 2014 39 163 176 10.1159/000358904 24862019

91. Palmer S. Albergante L. Blackburn C.C. Newman T.J. Thymic involution and rising disease incidence with age Proc. Natl. Acad. Sci. USA 2018 115 1883 1888 10.1073/pnas.1714478115 29432166 PMC5828591

92. Accardi G. Caruso C. Immune-inflammatory responses in the elderly: An update Immun. Ageing 2018 15 11 10.1186/s12979-018-0117-8 29507595 PMC5833087

93. Patsoukis N. Bardhan K. Chatterjee P. Sari D. Liu B. Bell L.N. Karoly E.D. Freeman G.J. Petkova V. Seth P. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation Nat. Commun. 2015 6 6692 10.1038/ncomms7692 25809635 PMC4389235

94. Henson S.M. Lanna A. Riddell N.E. Franzese O. Macaulay R. Griffiths S.J. Puleston D.J. Watson A.S. Simon A.K. Tooze S.A. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells J. Clin. Investig. 2014 124 4004 4016 10.1172/jci75051 25083993 PMC4151208

95. Thomas R. Wang W. Su D.M. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging Immun. Ageing 2020 17 2 10.1186/s12979-020-0173-8 31988649 PMC6971920

96. Palmer D.B. The effect of age on thymic function Front. Immunol. 2013 4 316 10.3389/fimmu.2013.00316 24109481 PMC3791471

97. Goronzy J.J. Weyand C.M. Understanding immunosenescence to improve responses to vaccines Nat. Immunol. 2013 14 428 436 10.1038/ni.2588 23598398 PMC4183346

98. Pawelec G. Hallmarks of human “immunosenescence”: Adaptation or dysregulation? Immun. Ageing 2012 9 15 10.1186/1742-4933-9-15 22830639 PMC3416738

99. Flores K.G. Li J. Sempowski G.D. Haynes B.F. Hale L.P. Analysis of the human thymic perivascular space during aging J. Clin. Investig. 1999 104 1031 1039 10.1172/jci7558 10525041 PMC408578

100. Lynch H.E. Goldberg G.L. Chidgey A. Van den Brink M.R. Boyd R. Sempowski G.D. Thymic involution and immune reconstitution Trends Immunol. 2009 30 366 373 10.1016/j.it.2009.04.003 19540807 PMC2750859

101. Wertheimer A.M. Bennett M.S. Park B. Uhrlaub J.L. Martinez C. Pulko V. Currier N.L. Nikolich-Žugich D. Kaye J. Nikolich-Žugich J. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans J. Immunol. 2014 192 2143 2155 10.4049/jimmunol.1301721 24501199 PMC3989163

102. Fulop T. Larbi A. Dupuis G. Le Page A. Frost E.H. Cohen A.A. Witkowski J.M. Franceschi C. Immunosenescence and Inflamm-Aging as Two Sides of the Same Coin: Friends or Foes? Front. Immunol. 2017 8 1960 10.3389/fimmu.2017.01960 29375577 PMC5767595

103. Feldman N. Rotter-Maskowitz A. Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies Ageing Res. Rev. 2015 24 29 39 10.1016/j.arr.2015.01.003 25641058

104. Effros R.B. Dagarag M. Spaulding C. Man J. The role of CD8+ T-cell replicative senescence in human aging Immunol. Rev. 2005 205 147 157 10.1111/j.0105-2896.2005.00259.x 15882351

105. Ershler W.B. Keller E.T. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty Annu. Rev. Med. 2000 51 245 270 10.1146/annurev.med.51.1.245 10774463

106. Bruunsgaard H. Andersen-Ranberg K. Hjelmborg J. Pedersen B.K. Jeune B. Elevated levels of tumor necrosis factor alpha and mortality in centenarians Am. J. Med. 2003 115 278 283 10.1016/s0002-9343(03)00329-2 12967692

107. Ferrucci L. Fabbri E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty Nat. Rev. Cardiol. 2018 15 505 522 10.1038/s41569-018-0064-2 30065258 PMC6146930

108. Takasugi M. Okada R. Takahashi A. Virya Chen D. Watanabe S. Hara E. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2 Nat. Commun. 2017 8 15729 10.1038/ncomms15728 PMC5467215 28585531

109. Acosta J.C. Banito A. Wuestefeld T. Georgilis A. Janich P. Morton J.P. Athineos D. Kang T.W. Lasitschka F. Andrulis M. A complex secretory program orchestrated by the inflammasome controls paracrine senescence Nat. Cell Biol. 2013 15 978 990 10.1038/ncb2784 23770676 PMC3732483

110. Faget D.V. Ren Q. Stewart S.A. Unmasking senescence: Context-dependent effects of SASP in cancer Nat. Rev. Cancer 2019 19 439 453 10.1038/s41568-019-0156-2 31235879

111. Yi F. Frazzette N. Cruz A.C. Klebanoff C.A. Siegel R.M. Beyond Cell Death: New Functions for TNF Family Cytokines in Autoimmunity and Tumor Immunotherapy Trends Mol. Med. 2018 24 642 653 10.1016/j.molmed.2018.05.004 29880309 PMC7466867

112. Okoye I.S. Xu L. Walker J. Elahi S. The glucocorticoids prednisone and dexamethasone differentially modulate T cell function in response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade Cancer Immunol. Immunother. 2020 69 1423 1436 10.1007/s00262-020-02555-2 32246174 PMC11027618

113. Gong W. Hoffmann J.M. Stock S. Wang L. Liu Y. Schubert M.L. Neuber B. Hückelhoven-Krauss A. Gern U. Schmitt A. Comparison of IL-2 vs IL-7/IL-15 for the generation of NY-ESO-1-specific T cells Cancer Immunol. Immunother. 2019 68 1195 1209 10.1007/s00262-019-02354-4 31177329 PMC11028180

114. d’Adda di Fagagna F. Living on a break: Cellular senescence as a DNA-damage response Nat. Rev. Cancer 2008 8 512 522 10.1038/nrc2440 18574463

115. Kang T.W. Yevsa T. Woller N. Hoenicke L. Wuestefeld T. Dauch D. Hohmeyer A. Gereke M. Rudalska R. Potapova A. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development Nature 2011 479 547 551 10.1038/nature10599 22080947

116. Kumari N. Dwarakanath B.S. Das A. Bhatt A.N. Role of interleukin-6 in cancer progression and therapeutic resistance Tumour Biol. 2016 37 11553 11572 10.1007/s13277-016-5098-7 27260630

117. Liu Y.X. Xu B.W. Chen Y.J. Fu X.Q. Zhu P.L. Bai J.X. Chou J.Y. Yin C.L. Li J.K. Wang Y.P. Inhibiting the Src/STAT3 signaling pathway contributes to the anti-melanoma mechanisms of dioscin Oncol. Lett. 2020 19 2508 2514 10.3892/ol.2020.11315 32194752 PMC7039043

118. So J.Y. Skrypek N. Yang H.H. Merchant A.S. Nelson G.W. Chen W.D. Ishii H. Chen J.M. Hu G. Achyut B.R. Induction of DNMT3B by PGE2 and IL6 at Distant Metastatic Sites Promotes Epigenetic Modification and Breast Cancer Colonization Cancer Res. 2020 80 2612 2627 10.1158/0008-5472.Can-19-3339 32265226 PMC7299749

119. Patel H.J. Patel B.M. TNF-α and cancer cachexia: Molecular insights and clinical implications Life Sci. 2017 170 56 63 10.1016/j.lfs.2016.11.033 27919820

120. Eggert T. Wolter K. Ji J. Ma C. Yevsa T. Klotz S. Medina-Echeverz J. Longerich T. Forgues M. Reisinger F. Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression Cancer Cell 2016 30 533 547 10.1016/j.ccell.2016.09.003 27728804 PMC7789819

121. Maynard J.P. Ertunc O. Kulac I. Baena-Del Valle J.A. De Marzo A.M. Sfanos K.S. IL8 Expression Is Associated with Prostate Cancer Aggressiveness and Androgen Receptor Loss in Primary and Metastatic Prostate Cancer Mol. Cancer Res. 2020 18 153 165 10.1158/1541-7786.Mcr-19-0595 31604846

122. Campisi J. Aging, cellular senescence, and cancer Annu. Rev. Physiol. 2013 75 685 705 10.1146/annurev-physiol-030212-183653 23140366 PMC4166529

123. Doran M.F. Pond G.R. Crowson C.S. O’Fallon W.M. Gabriel S.E. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period Arthritis Rheum. 2002 46 625 631 10.1002/art.509 11920397

124. Nikolich-Žugich J. Aging of the T cell compartment in mice and humans: From no naive expectations to foggy memories J. Immunol. 2014 193 2622 2629 10.4049/jimmunol.1401174 25193936 PMC4157314

125. Sceneay J. Goreczny G.J. Wilson K. Morrow S. DeCristo M.J. Ubellacker J.M. Qin Y. Laszewski T. Stover D.G. Barrera V. Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer Cancer Discov. 2019 9 1208 1227 10.1158/2159-8290.Cd-18-1454 31217296 PMC11167954

126. Ye J. Ma C. Hsueh E.C. Eickhoff C.S. Zhang Y. Varvares M.A. Hoft D.F. Peng G. Tumor-derived γδ regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence J. Immunol. 2013 190 2403 2414 10.4049/jimmunol.1202369 23355732 PMC3578061

127. Liu X. Mo W. Ye J. Li L. Zhang Y. Hsueh E.C. Hoft D.F. Peng G. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition Nat. Commun. 2018 9 249 10.1038/s41467-017-02689-5 29339767 PMC5770447

128. Wang D. Yang L. Yue D. Cao L. Li L. Wang D. Ping Y. Shen Z. Zheng Y. Wang L. Macrophage-derived CCL22 promotes an immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion Cancer Lett. 2019 452 244 253 10.1016/j.canlet.2019.03.040 30928379

129. Yang L. Zhang Y. Tumor-associated macrophages: From basic research to clinical application J. Hematol. Oncol. 2017 10 58 10.1186/s13045-017-0430-2 28241846 PMC5329931

130. Wang W. Chen J.X. Liao R. Deng Q. Zhou J.J. Huang S. Sun P. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence Mol. Cell Biol. 2002 22 3389 3403 10.1128/mcb.22.10.3389-3403.2002 11971971 PMC133789

131. Freund A. Patil C.K. Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype EMBO J. 2011 30 1536 1548 10.1038/emboj.2011.69 21399611 PMC3102277

132. Liu X. Si F. Bagley D. Ma F. Zhang Y. Tao Y. Shaw E. Peng G. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy J. Immunother. Cancer 2022 10 e005020 10.1136/jitc-2022-005020 36192086 PMC9535198

133. Pu Y. Ji Q. Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression Front. Immunol. 2022 13 874589 10.3389/fimmu.2022.874589 35592338 PMC9110638

134. Lanna A. Henson S.M. Escors D. Akbar A.N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells Nat. Immunol. 2014 15 965 972 10.1038/ni.2981 25151490 PMC4190666

135. Muller W.A. Localized signals that regulate transendothelial migration Curr. Opin. Immunol. 2016 38 24 29 10.1016/j.coi.2015.10.006 26584476 PMC4715928

136. Slaney C.Y. Kershaw M.H. Darcy P.K. Trafficking of T cells into tumors Cancer Res. 2014 74 7168 7174 10.1158/0008-5472.Can-14-2458 25477332

137. Hughes P.E. Caenepeel S. Wu L.C. Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer Trends Immunol. 2016 37 462 476 10.1016/j.it.2016.04.010 27216414

138. Zhang J. Yu J. Liu M. Xie Z. Lei X. Yang X. Huang S. Deng X. Wang Z. Tang G. Small-molecule modulators of tumor immune microenvironment Bioorg. Chem. 2024 145 107251 10.1016/j.bioorg.2024.107251 38442612

139. Bueno L. de Alwis D.P. Pitou C. Yingling J. Lahn M. Glatt S. Trocóniz I.F. Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice Eur. J. Cancer 2008 44 142 150 10.1016/j.ejca.2007.10.008 18039567

140. Jin C.H. Krishnaiah M. Sreenu D. Subrahmanyam V.B. Rao K.S. Lee H.J. Park S.J. Park H.J. Lee K. Sheen Y.Y. Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent J. Med. Chem. 2014 57 4213 4238 10.1021/jm500115w 24786585

141. Xu H. Zhao X.L. Liu X. Hu X.G. Fu W.J. Li Q. Wang Y. Ping Y.F. Zhang X. Bian X.W. Elevated ASCL2 expression in breast cancer is associated with the poor prognosis of patients Am. J. Cancer Res. 2017 7 955 961 28469967 PMC5411802

142. Ferrara R. Mezquita L. Auclin E. Chaput N. Besse B. Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter? Cancer Treat. Rev. 2017 60 60 68 10.1016/j.ctrv.2017.08.003 28889085

143. Kennedy B.K. Berger S.L. Brunet A. Campisi J. Cuervo A.M. Epel E.S. Franceschi C. Lithgow G.J. Morimoto R.I. Pessin J.E. Geroscience: Linking aging to chronic disease Cell 2014 159 709 713 10.1016/j.cell.2014.10.039 25417146 PMC4852871

144. Shalapour S. Karin M. Pas de Deux: Control of Anti-tumor Immunity by Cancer-Associated Inflammation Immunity 2019 51 15 26 10.1016/j.immuni.2019.06.021 31315033 PMC6640850

145. Kugel C.H. 3rd Douglass S.M. Webster M.R. Kaur A. Liu Q. Yin X. Weiss S.A. Darvishian F. Al-Rohil R.N. Ndoye A. Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations Clin. Cancer Res. 2018 24 5347 5356 10.1158/1078-0432.Ccr-18-1116 29898988 PMC6324578

146. Rodriguez J.E. Naigeon M. Goldschmidt V. Roulleaux Dugage M. Seknazi L. Danlos F.X. Champiat S. Marabelle A. Michot J.M. Massard C. Immunosenescence, inflammaging, and cancer immunotherapy efficacy Expert. Rev. Anticancer. Ther. 2022 22 915 926 10.1080/14737140.2022.2098718 35815381

147. Marur S. Singh H. Mishra-Kalyani P. Larkins E. Keegan P. Sridhara R. Blumenthal G.M. Pazdur R. FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies Semin. Oncol. 2018 45 220 225 10.1053/j.seminoncol.2018.08.007 30391014

148. Elias R. Giobbie-Hurder A. McCleary N.J. Ott P. Hodi F.S. Rahma O. Efficacy of PD-1 & PD-L1 inhibitors in older adults: A meta-analysis J. Immunother. Cancer 2018 6 26 10.1186/s40425-018-0336-8 29618381 PMC5885356

149. Nishijima T.F. Muss H.B. Shachar S.S. Moschos S.J. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis Cancer Treat. Rev. 2016 45 30 37 10.1016/j.ctrv.2016.02.006 26946217

150. Ridolfi L. De Rosa F. Petracci E. Tanda E.T. Marra E. Pigozzo J. Marconcini R. Guida M. Cappellini G.C.A. Gallizzi G. Anti-PD1 antibodies in patients aged ≥ 75 years with metastatic melanoma: A retrospective multicentre study J. Geriatr. Oncol. 2020 11 515 522 10.1016/j.jgo.2019.12.012 31928943

151. Fu Z. Xu H. Yue L. Zheng W. Pan L. Gao F. Liu X. Immunosenescence and cancer: Opportunities and challenges Medicine 2023 102 e36045 10.1097/md.0000000000036045 38013358 PMC10681516

152. Hou C. Wang Z. Lu X. Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors Cancer Pathog. Ther. 2024 2 24 30 10.1016/j.cpt.2023.08.001 38328711 PMC10846300

153. McCay C.M. Maynard L.A. Sperling G. Barnes L.L. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories Nutr. Rev. 1975 33 241 243 10.1111/j.1753-4887.1975.tb05227.x 1095975

154. Mattison J.A. Colman R.J. Beasley T.M. Allison D.B. Kemnitz J.W. Roth G.S. Ingram D.K. Weindruch R. de Cabo R. Anderson R.M. Caloric restriction improves health and survival of rhesus monkeys Nat. Commun. 2017 8 14063 10.1038/ncomms14063 28094793 PMC5247583

155. Pifferi F. Terrien J. Marchal J. Dal-Pan A. Djelti F. Hardy I. Chahory S. Cordonnier N. Desquilbet L. Hurion M. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates Commun. Biol. 2018 1 30 10.1038/s42003-018-0024-8 30271916 PMC6123706

156. Omodei D. Fontana L. Calorie restriction and prevention of age-associated chronic disease FEBS Lett. 2011 585 1537 1542 10.1016/j.febslet.2011.03.015 21402069 PMC3439843

157. Campisi J. Kapahi P. Lithgow G.J. Melov S. Newman J.C. Verdin E. From discoveries in ageing research to therapeutics for healthy ageing Nature 2019 571 183 192 10.1038/s41586-019-1365-2 31292558 PMC7205183

158. Pignolo R.J. Passos J.F. Khosla S. Tchkonia T. Kirkland J.L. Reducing Senescent Cell Burden in Aging and Disease Trends Mol. Med. 2020 26 630 638 10.1016/j.molmed.2020.03.005 32589933 PMC7857028

159. Kim M.J. Miller C.M. Shadrach J.L. Wagers A.J. Serwold T. Young, proliferative thymic epithelial cells engraft and function in aging thymuses J. Immunol. 2015 194 4784 4795 10.4049/jimmunol.1403158 25870244 PMC4481326

160. Sun L. Guo J. Brown R. Amagai T. Zhao Y. Su D.M. Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution Aging Cell 2010 9 347 357 10.1111/j.1474-9726.2010.00559.x 20156205 PMC2894280

161. Henson S.M. Snelgrove R. Hussell T. Wells D.J. Aspinall R. An IL-7 fusion protein that shows increased thymopoietic ability J. Immunol. 2005 175 4112 4118 10.4049/jimmunol.175.6.4112 16148161

162. Su D.M. Aw D. Palmer D.B. Immunosenescence: A product of the environment? Curr. Opin. Immunol. 2013 25 498 503 10.1016/j.coi.2013.05.018 23809359

163. Huff W.X. Kwon J.H. Henriquez M. Fetcko K. Dey M. The Evolving Role of CD8(+)CD28(-) Immunosenescent T Cells in Cancer Immunology Int. J. Mol. Sci. 2019 20 2810 10.3390/ijms20112810 31181772 PMC6600236

164. Muñoz-Lorente M.A. Cano-Martin A.C. Blasco M.A. Mice with hyper-long telomeres show less metabolic aging and longer lifespans Nat. Commun. 2019 10 4723 10.1038/s41467-019-12664-x 31624261 PMC6797762

165. Lanna A. Vaz B. D’Ambra C. Valvo S. Vuotto C. Chiurchiù V. Devine O. Sanchez M. Borsellino G. Akbar A.N. An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory Nat. Cell Biol. 2022 24 1461 1474 10.1038/s41556-022-00991-z 36109671 PMC7613731

166. Fauce S.R. Jamieson B.D. Chin A.C. Mitsuyasu R.T. Parish S.T. Ng H.L. Kitchen C.M. Yang O.O. Harley C.B. Effros R.B. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes J. Immunol. 2008 181 7400 7406 10.4049/jimmunol.181.10.7400 18981163 PMC2682219

167. Giallongo C. Parrinello N.L. La Cava P. Camiolo G. Romano A. Scalia M. Stagno F. Palumbo G.A. Avola R. Li Volti G. Monocytic myeloid-derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib J. Cell Mol. Med. 2018 22 1070 1080 10.1111/jcmm.13326 29218828 PMC5783858

168. Li L. Liu X. Sanders K.L. Edwards J.L. Ye J. Si F. Gao A. Huang L. Hsueh E.C. Ford D.A. TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy Cell Metab. 2019 29 103 123.e105 10.1016/j.cmet.2018.09.020 30344014 PMC7050437

169. Ye J. Huang X. Hsueh E.C. Zhang Q. Ma C. Zhang Y. Varvares M.A. Hoft D.F. Peng G. Human regulatory T cells induce T-lymphocyte senescence Blood 2012 120 2021 2031 10.1182/blood-2012-03-416040 22723548 PMC3437594

170. Zhan J.K. Wang Y.J. Li S. Wang Y. Tan P. He J.Y. Chen Y.Y. Deng H.Q. Huang W. Lin X. AMPK/TSC2/mTOR pathway regulates replicative senescence of human vascular smooth muscle cells Exp. Ther. Med. 2018 16 4853 4858 10.3892/etm.2018.6767 30542441 PMC6257130

171. Kusumoto D. Seki T. Sawada H. Kunitomi A. Katsuki T. Kimura M. Ito S. Komuro J. Hashimoto H. Fukuda K. Anti-senescent drug screening by deep learning-based morphology senescence scoring Nat. Commun. 2021 12 257 10.1038/s41467-020-20213-0 33431893 PMC7801636

172. Charron D. Autologous white blood cell transfusion: Toward a younger immunity Hum. Immunol. 2007 68 805 812 10.1016/j.humimm.2007.07.004 17961768

173. Barzilai N. Crandall J.P. Kritchevsky S.B. Espeland M.A. Metformin as a Tool to Target Aging Cell Metab. 2016 23 1060 1065 10.1016/j.cmet.2016.05.011 27304507 PMC5943638

174. Bannister C.A. Holden S.E. Jenkins-Jones S. Morgan C.L. Halcox J.P. Schernthaner G. Mukherjee J. Currie C.J. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls Diabetes Obes. Metab. 2014 16 1165 1173 10.1111/dom.12354 25041462

175. Strong R. Miller R.A. Antebi A. Astle C.M. Bogue M. Denzel M.S. Fernandez E. Flurkey K. Hamilton K.L. Lamming D.W. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer Aging Cell 2016 15 872 884 10.1111/acel.12496 27312235 PMC5013015

176. Martin-Montalvo A. Mercken E.M. Mitchell S.J. Palacios H.H. Mote P.L. Scheibye-Knudsen M. Gomes A.P. Ward T.M. Minor R.K. Blouin M.J. Metformin improves healthspan and lifespan in mice Nat. Commun. 2013 4 2192 10.1038/ncomms3192 23900241 PMC3736576

177. Kapahi P. Chen D. Rogers A.N. Katewa S.D. Li P.W. Thomas E.L. Kockel L. With TOR, less is more: A key role for the conserved nutrient-sensing TOR pathway in aging Cell Metab. 2010 11 453 465 10.1016/j.cmet.2010.05.001 20519118 PMC2885591

178. Ha C.W. Huh W.K. Rapamycin increases rDNA stability by enhancing association of Sir2 with rDNA in Saccharomyces cerevisiae Nucleic Acids Res. 2011 39 1336 1350 10.1093/nar/gkq895 20947565 PMC3045593

179. Harrison D.E. Strong R. Sharp Z.D. Nelson J.F. Astle C.M. Flurkey K. Nadon N.L. Wilkinson J.E. Frenkel K. Carter C.S. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice Nature 2009 460 392 395 10.1038/nature08221 19587680 PMC2786175

180. Miller R.A. Harrison D.E. Astle C.M. Baur J.A. Boyd A.R. de Cabo R. Fernandez E. Flurkey K. Javors M.A. Nelson J.F. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice J. Gerontol. A Biol. Sci. Med. Sci. 2011 66 191 201 10.1093/gerona/glq178 20974732 PMC3021372

181. Popovich I.G. Anisimov V.N. Zabezhinski M.A. Semenchenko A.V. Tyndyk M.L. Yurova M.N. Blagosklonny M.V. Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin Cancer Biol. Ther. 2014 15 586 592 10.4161/cbt.28164 24556924 PMC4026081

182. Xu J. Pham C.G. Albanese S.K. Dong Y. Oyama T. Lee C.H. Rodrik-Outmezguine V. Yao Z. Han S. Chen D. Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin J. Clin. Investig. 2016 126 3526 3540 10.1172/jci86120 27482884 PMC5004947

183. Sung J.Y. Lee K.Y. Kim J.R. Choi H.C. Interaction between mTOR pathway inhibition and autophagy induction attenuates adriamycin-induced vascular smooth muscle cell senescence through decreased expressions of p53/p21/p16 Exp. Gerontol. 2018 109 51 58 10.1016/j.exger.2017.08.001 28797827