The progress and perspective of nanomedicine in modulating the tumor immune microenvironment.

Introduction

The tumor immune microenvironment (TIM) is a multifaceted and dynamic ecosystem in which neoplastic cells interact with immune cells, the extracellular matrix (ECM), and various signaling molecules. In contrast to the normal immune microenvironment, which is tasked with maintaining immune surveillance and eliminating abnormal cells, the TIM is characterized by its immunosuppressive properties, chronic inflammatory nature, and distinctive tumor metabolic features. This complex environment significantly influences cancer progression, metastasis, and response to therapy. The TIM acts as both a physical barrier to immune cell infiltration and as an active contributor to the suppression of anti-tumor immunity through the secretion of immunosuppressive cytokines and the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) 1 , 2 . A profound understanding of the TIM's intricacies is essential for developing effective cancer combat strategies.

Nanomedicine is a broad field that leverages nanotechnology to prevent, monitor, and intervene in diseases through new modes of imaging, diagnosing, treating, repairing, and regenerating biological systems. The scope of nanomedicine is not limited to nanoparticles; it also encompasses nanorobots and a variety of nanoscale tools, such as liposomes, polymer micelles, and other targeted delivery systems. Engineered nanomedicine can penetrate the dense extracellular matrix (ECM) of tumors, deliver immunomodulatory agents directly to the tumor site, and counteract the immunosuppressive characteristics of the TIM 3 . The ability of nanomedicine to enhance the efficacy of immunotherapies by normalizing vasculature and improving immune cell penetration into the tumor is a subject of intense research 4 . The advantages of nanomedicine in TIM therapy are multifaceted. For instance, nanosized particles are more effectively uptaken by antigen-presenting cells (APCs), which is crucial for activating the immune response 5 . Additionally, the targeted delivery of chemotherapeutic agents using nanocarriers can reduce systemic toxicity while increasing local drug concentration, thus enhancing the therapeutic index of cancer treatment. Moreover, the use of multifunctional bio-nanostructures in cancer therapy has been a focus of extensive research, with these structures showing promise in drug targeting, controllable drug release, and efficient transport within the complex tumor microenvironment 6 .

This review aims to comprehensively outline the current progress and prospects of nanomedicine in modulating the TIM. We will discuss various nanomedicine-based strategies being explored to enhance the effectiveness of cancer immunotherapy. Additionally, we will highlight the challenges associated with nanomedicine development, such as the need for improved targeting, reduced off-target effects, and the optimization of nanomedicine design for enhanced biocompatibility and biodegradability. Furthermore, we will explore the clinical implications of these strategies and the potential for personalized nanomedicine in light of the heterogeneous nature of the TIM. By contrasting the frontiers and differences between basic scientific research and clinical applications, we hope to provide insights into the next steps in the development of nanomaterials for the tumor immune microenvironment.

Overview of the tumor immune microenvironment

The TIM is a complex and enigmatic arena where immune cells, cancer cells, and non-hematopoietic stromal cells engage in a continuous interplay that influences tumor progression and response to therapy 7 , 8 . The TIM encompasses immune cells including T cells, B cells, macrophages, and dendritic cells, along with non-immunological components such as fibroblasts, endothelial cells, and the ECM 9 . Tumor-infiltrating lymphocytes (TILs) are immune cells that have migrated from the bloodstream into the tumor microenvironment (TME) ( Fig. 1 ). TILs play a crucial role in the immune response against tumors and can exert both beneficial and detrimental effects on tumor growth and progression. The presence and composition of TILs within tumors have been associated with clinical outcomes in cancer patients. Elevated levels of TILs, especially cytotoxic CD8 + T cells, have been linked to improved prognosis and enhanced response to immunotherapy in specific cancer types. Conversely, tumors with low TIL levels or an immunosuppressive microenvironment may evade immune surveillance and develop resistance to treatment. Figure 1 Immune Modulation in Tumor Microenvironment. Natural killer (NK) cells and CD8 + T cells play a crucial role in immune activation and cytotoxic attack on tumor cells, producing pro-inflammatory cytokines such as interferon-gamma (IFN- γ ) and activating antigen-specific T-cell responses. Dendritic cells (DC) and M1 tumor-associated macrophages (M1 TAM) contribute to immune activation through the production of cytokines and cytotoxic molecules like perforin and granzyme. Myeloid-derived suppressor cells (MDSC) and M2 tumor-associated macrophages (M2 TAM) are associated with immune suppression, secreting immunosuppressive cytokines like IL-10 and TGF- β , which block the expansion of cytotoxic T lymphocytes (CTLs) and NK cells. They also stimulate angiogenesis and tissue remodeling, promoting a pro-tumor effect. Regulatory T cells (Treg) and cancer-associated fibroblasts (CAF) further contribute to immune suppression through multiple mechanisms, including control of inflammatory conditions, suppression of CTL activation and expansion, metabolic disruption, tissue remodeling and angiogenesis, which are essential for tumor growth and progression. Figure 1

T cells in the TIM

T cells play a crucial role in mounting immune responses against tumors. T cells can be broadly classified based on their T cell receptor (TCR) subunits and the expression of core lineage markers such as CD8 and CD4 10 . The αβ TCR complex, present in CD8 and CD4 T cells, allows recognition of peptides presented on the cell surface in the context of major histocompatibility complex (MHC) class I or class II, respectively. On the other hand, γδ T cells, characterized by the γδ TCR subunit, function independently of MHC classes I and II. In tumor tissues, CD8 + and CD4 + TCR αβ T cells are the most abundant T cell subsets.

CD8 + T cells, also known as cytotoxic T lymphocytes (CTL), are primarily responsible for recognizing and destroying tumor cells 11 . They recognize specific antigens presented on major histocompatibility complex class I (MHC-I) molecules expressed on the surface of cancer cells. Upon activation, CD8 + T cells undergo clonal expansion, generating a large population of effector CD8 + T cells capable of directly eliminating tumor cells 12 . They achieve this through the release of cytotoxic molecules, such as perforin and granzymes, which induce apoptosis (programmed cell death) in the target cells. CD8 + T cells also produce and release cytokines, such as interferon-gamma (IFN- γ ) and tumor necrosis factor-alpha (TNF- α ) 13 , 14 . IFN- γ activates other immune cells and enhances immune surveillance, contributing to the antitumor immune response, while TNF- α induces tumor cell apoptosis and stimulates immune cell activity to clear tumor cells. However, in the TIM, CD8 + T cells can also encounter immune inhibitory signals that dampen their function. Tumor cells often exploit immune checkpoint pathways, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), to evade immune destruction 15 . Interaction of these inhibitory receptors with their ligands on tumor cells leads to T cell exhaustion, a state of functional impairment characterized by reduced cytokine production and cytotoxic activity. Immunotherapies targeting immune checkpoint molecules, known as immune checkpoint blockade (ICB), have been developed to block the inhibitory signals and restore the activity of CD8 + T cells, leading to enhanced tumor cell killing 16 .

CD4 + T cells, or helper T cells, express the CD4 co-receptor on their cell surface and play crucial roles in coordinating and regulating immune responses 17 . They differentiate into various subsets based on their cytokine profiles and transcription factors, including Th1, Th2, Th17, Tregs, and follicular helper T cells (Tfh) 18 . Th1 cells produce cytokines such as IFN- γ and TNF- α , which promote cellular immune responses and enhance the activity of cytotoxic CD8 + T cells and macrophages 19 . Th2 cells produce cytokines such as interleukin (IL)-4, IL-5, and IL-13, which are involved in promoting humoral immune responses. While Th2 responses are typically associated with allergic and parasitic diseases, they can also play a role in certain tumor contexts 20 . Th17 cells produce cytokines such as IL-17 and IL-22 and are implicated in inflammation and tissue remodeling 21 . In the TIM, Th17 cells can have both pro- and antitumor effects. Tfh cells are specialized CD4 + T cells that provide help to B cells in generating antibody responses 22 . Within the TIM, Tfh cells can contribute to the formation of tertiary lymphoid structures (TLSs), which are organized lymphoid-like structures observed in some tumors. TLSs can facilitate immune cell interactions and promote antitumor immune responses 23 .

B cells in the TIM

B cells are a critical component of the adaptive immune system. Within the TIM, tumor-infiltrating B cells (TIL-Bs) display significant heterogeneity and can exert both pro-tumorigenic and anti-tumorigenic effects. TIL-Bs directly influence the anti-tumor immune response through antibody production, antigen presentation, and interaction with other immune cells. TIL-Bs display characteristic features of an active immune response, including antigen recognition, clonal expansion, phenotypic differentiation, and the production of somatically hypermutated, class-switched antibodies with anti-tumor properties 24 .

Firstly, B cells exhibit anti-tumor effects. B cells can recognize tumor-specific antigens and generate antibodies that can bind to and neutralize tumor cells. These antibodies can directly eliminate tumor cells, induce complement-mediated cytotoxicity, or stimulate other immune cells to participate in antibody-dependent cellular cytotoxicity (ADCC). Moreover, B cells can function as APCs within tumors 25 . B cells can process and present antigenic peptides to CD4 + T cells through the MHC class II pathway 26 , and also cross-present peptide-MHC I complexes to activate CD8 + T cells 27 . Notably, B cells utilize their surface immunoglobulin to efficiently capture and internalize cognate antigens, allowing them to present low-abundance antigens to T cells more effectively compared to dendritic cells or macrophages 28 , 29 . TLSs, also known as ectopic lymphoid organs, are commonly found in the peritumoral stromal regions of highly immunogenic tumors 30 .

Conversely, B cells can also demonstrate protumor functions within the tumor immune microenvironment. Specific subsets of B cells, termed regulatory B cells (Bregs), possess immunosuppressive properties 31 . Bregs secrete immunosuppressive cytokines such as IL-10, IL-35, and transforming growth factor beta (TGF- β ), or release metabolites such as gamma-aminobutyric acid (GABA), which suppress antitumor immune responses and foster immune tolerance 32 , 33 , 34 . Additionally, tumor cells can exploit B cells and antibodies to evade immune surveillance. They can express molecules that bind to the Fc portion of antibodies, preventing their effector functions and neutralization of tumor cells. This mechanism is known as antibody-mediated immune evasion. Additionally, B cells can produce growth factors that promote tumor growth, angiogenesis, and metastasis.

Nature killer (NK) cells

Natural killer (NK) cells are a critical component of the innate immune system, known for their ability to identify and eliminate tumor cells and infected cells without prior sensitization. They achieve this through a balance of signals received from activating and inhibitory receptors, which allows them to discriminate between healthy and stressed or transformed cells 35 .

Natural killer (NK) cells are equipped with a variety of activating and inhibitory receptors that play a pivotal role in identifying and eliminating target cells. Activating receptors such as NKG2D, DNAM-1, and NCRs (NKp30, NKp44, NKp46) are crucial for the recognition of target cells, while inhibitory receptors like KIRs and NKG2A interact with MHC class I molecules, maintaining self-tolerance and preventing the NK cells from attacking healthy cells 36 .

The activating receptor NKG2D, for instance, is alerted to the presence of cancer cells by the upregulation of its ligands ULBP1 and ULBP2, which is often associated with cellular stress and malignancy. DNAM-1, another activating receptor, is implicated in the NK cell-mediated response against certain tumors and viral infections. Meanwhile, the NCRs, including NKp30, NKp44, and NKp46, contribute to the immediate cytotoxic response against target cells that lack or have downregulated MHC class I molecules, which is a common mechanism of immune evasion in virally infected and malignant cells 37 .

On the other hand, inhibitory receptors are equally important for a balanced immune response. Killer cell immunoglobulin-like receptors (KIRs) are one such family of receptors that bind to MHC class I molecules on cells, sending inhibitory signals to prevent the lysis of healthy self-cells. The NKG2A receptor, part of the natural killer group 2 complex, also plays a role in inhibiting NK cell activation, thus helping to avoid overzealous immune responses against the body's tissues 38 , 39 .

The balance between these activating and inhibitory signals is critical for the proper functioning of NK cells. When the activating signals outweigh the inhibitory signals, NK cells become activated and initiate their cytotoxic functions, leading to the release of cytotoxic granules containing perforin and granzymes, which induce apoptosis in target cells. Moreover, NK cells can also mediate antibody-dependent cellular cytotoxicity (ADCC) through their Fc receptors, such as CD16, which bind to the Fc portion of antibodies that are attached to target cells 40 .

Tumor-associated macrophages (TAMs)

Macrophages originate from myeloid progenitor cells in the bone marrow and monocytes circulating in the blood. These precursor cells migrate into tissues and differentiate into mature macrophages. Notably, specialized macrophage populations in tissues such as the lungs and liver originate from embryonic progenitors 41 , 42 , 43 . TAMs, which infiltrate tumor tissues or reside within the solid tumor microenvironment 44 , play a central role in establishing an immunosuppressive TME.

TAMs can be broadly categorized as M1 and M2 macrophages based on their polarized phenotypes and distinct functional roles 45 . M1 TAMs exhibit anti-tumor properties, promoting inflammation and cytotoxicity by secreting pro-inflammatory cytokines like IL-12, IL-1 β , IL-6, IL-23, CXCL-10, IFN- γ , and tumor necrosis factor (TNF- α ), and generating nitric oxide (NO) and reactive oxygen species (ROS) 46 . Conversely, M2 TAMs secrete immunosuppressive cytokines such as IL-13, IL-4, and IL-10, transforming growth factor (TGF- β ), and matrix metalloproteinases (MMPs) including MMP-2 and MMP-9, as well as growth factors like vascular endothelial growth factor (VEGF). They also express arginase-1, mannose receptor, and scavenger receptors, which contribute to their pro-tumorigenic properties and immunosuppressive role 47 , 48 , 49 .

The recruitment and polarization of macrophages are regulated by intricate biological networks. Colony-stimulating factor-1 (CSF-1), C-C motif ligand 2 (CCL2), VEGF-A, and EGFR are well-studied factors that promote macrophage recruitment and polarization towards the M2 phenotype 50 , 51 , 52 . Additionally, monocytes are recruited into tumor tissues under the influence of various cytokines, chemokines, and growth factors such as CCL7, CCL8, CCL3, CCL4, granulocyte-macrophage CSF (GM-CSF), macrophage-stimulating protein (MSP), platelet-derived growth factor (PDGF), and TGF- β 1. They may then differentiate into immunosuppressive M2 TAMs in response to IL-4, IL-10, and IL-13 8 , 53 .

Furthermore, TAMs can accumulate in tumor tissues through the influence of hypoxia-induced factors and metabolites, including CCL2, CCL5, CSF-1, VEGF, semaphorin 3A, endothelial cell monocyte-activating polypeptide-II, endothelin, stromal cell-derived factor 1, eotaxin, oncostatin M, lactate, and angiopoietin-2 54 . It is noteworthy that various epigenetic regulators have been implicated in the accumulation, recruitment, and polarization of macrophages. For instance, protein arginine methyltransferase 1, SET and MYND domain-containing protein 3, Jumonji domain-containing protein 3, NAD-dependent protein deacetylase sirtuin-2, and bromodomain and extraterminal proteins positively regulate M2 polarization by upregulating M2 markers. In contrast, DNA methyltransferase 3B, Jumonji domain-containing protein 1A, histone deacetylase 3 (HDAC3), and HDAC 9 exert opposing effects 55 , 56 .

MDSCs

MDSCs represent a diverse group of innate immune cells that are activated under pathological conditions and are known for their robust immunosuppressive capabilities 57 . MDSCs are categorized into granulocytes/polymorphonuclear cells (G-MDSCs or PMN-MDSCs) and monocytes (M-MDSCs) 58 . They are rapidly elevated in the TIM during tumorigenesis 59 . MDSCs exert their immunosuppressive effects through multiple mechanisms, such as inhibiting T cell activation and proliferation, suppressing NK cell activity, promoting the development of regulatory T cells (Tregs), and dampening the functions of anti-tumor cells.

MDSCs can produce suppressive cytokines like TGF- β , IL-10, and immunosuppressive enzymes including arginase-1 (ARG1), ROS, iNOS, and PGE2 60 . They also express inhibitory cell surface molecules such as programmed death-ligand 1 (PD-L1). These inhibitory molecules and factors can disrupt the activation and proliferation of T cells and NK cells, enhance the proliferation of circulating tumor cells, promote epithelial-mesenchymal transition (EMT), and induce the expression of matrix metalloproteinases (MMPs) like MMP8 and MMP9, thereby fostering a pro-metastatic microenvironment 61 , 62 .

Furthermore, MDSCs can inhibit the activity of NK cells by producing suppressive cytokines and interacting with NK cells through cell surface molecules such as NKG2D ligands, thus impairing the killing function of NK cells 63 . MDSCs also promote the development of Tregs through the production of cytokines and interaction with molecules such as CTLA-4 and indoleamine 2,3-dioxygenase (IDO) 64 . Lastly, MDSCs can produce suppressive molecules such as acid proteases and oxidases, which directly inhibit the proliferation and function of anti-tumor cells.

Tregs

Tregs, a specialized subset of T cells, are defined by the expression of the transcription factor FoxP3 and the cell surface marker CD25. These cells are instrumental in preserving immune homeostasis and curbing excessive immune reactions. Tregs can be differentiated into several subpopulations, including non-activated Tregs, effector Tregs, and resting Tregs, which exhibit varying degrees of immunosuppressive capacity 65 . Within the TME, effector Tregs predominate, marked by heightened expression of surface markers such as CTLA-4, PD-1, OX40, and chemokine receptors. These markers facilitate tumor immune evasion 66 . The presence of Tregs within tumors correlates with adverse outcomes, including accelerated tumor growth, metastasis, and diminished responsiveness to immunotherapy. Tumor cells and the TME can enhance the recruitment and proliferation of Tregs by secreting chemokines and other immunosuppressive factors.

Tregs perform their immunosuppressive role through multiple mechanisms. A pivotal mechanism is the secretion of immunosuppressive cytokines, including IL-10, IL-35 (Ebi3–IL-12 α heterodimer), and TGF- β . These cytokines attenuate the activation and effector functions of other immune cells, such as cytotoxic CD8 + T cells, NK cells, and APCs 67 . Additionally, Tregs can suppress the function of other immune cells through direct cell-to-cell contact. They express molecules like CTLA-4 and lymphocyte activation gene 3 (LAG-3), which engage with co-stimulatory molecules on target cells, inhibiting their activation and function 68 , 69 , 70 , 71 . Moreover, the inhibitory receptors PD-1 and T cell immunoglobulin and ITIM domain (TIGIT) on Tregs can interact with their ligands on effector T cells, resulting in the functional impairment of these cells 72 . Tregs can also induce the expression of IDO in dendritic cells, converting tryptophan into kynurenine, which inhibits T cell proliferation and promoting apoptosis 71 , 73 . Furthermore, Tregs can directly induce apoptosis in effector T cells via the granzyme B/perforin pathway. However, it is essential to recognize that the role of Tregs in cancer is multifaceted and context-dependent. While Tregs are generally linked to immunosuppression and tumor-promoting effects, some subsets of Tregs may exhibit antitumor properties or display functions that vary with context.

Mechanisms of nanomedicine in modulating the TME

Nanoparticles, particles with dimensions typically ranging from 1 to 100 nm, can be fabricated from a variety of materials, including metals ( e.g. , gold, silver, copper, iron), polymers ( e.g. , poly(lactic- co -glycolic acid) (PLGA), polyethylene glycol (PEG), polystyrene (PS), poly(methyl methacrylate) (PMMA)), lipids, inorganic materials ( e.g. , silica (SiO 2 ), titanium dioxide (TiO 2 ), iron oxide (Fe 3 O 4 )), and composite materials 74 . The nanoscale dimensions endow these particles with distinctive physical, chemical, and biological properties that distinguish them from their bulk forms. Consequently, nanoparticles are a prevalent tool or constituent in nanomedicine. They can be tailored and functionalized to ensure targeted delivery, controlled release, and protection of drugs 75 . In general, the role of nanomedicine in TIM is not independent ( Fig. 2 ). Instead, various cells in the immune microenvironment can be influenced by the interaction of various factors. In the following, we will introduce the interaction of nanoparticles on immune cells with specific cell examples. Figure 2 Nanoparticle-mediated tumor immunotherapy. Nanoparticles are engineered to enhance immune cell expansion and deliver therapeutic agents to tumors. They actively target cancer cells, cross the blood–brain barrier, and facilitate gene delivery. These particles promote T cell proliferation and activation, overcome immune checkpoint inhibition, and exhibit smart behavior in response to tumor microenvironments. They also engage dendritic and NK cells, induce memory T cell formation, and respond to tumor fragments to amplify the immune response. This multi-pronged approach leverages nanoparticles to effectively combat tumors through a combination of direct cytotoxicity and immune system engagement. Figure 2

Interaction with T cells

Nanomedicine exhibits substantial potential in modulating the interactions between tumors and T cells, which are integral to the TME. Various mechanisms through which nanomedicine can influence T cell function and activity have been investigated. Nanomedicine can be precisely engineered to deliver immunomodulatory agents, such as checkpoint inhibitors, cytokines, or T cell costimulatory receptor agonists, directly to the TME. This targeted delivery strategy increases the local concentration of these agents while reducing systemic toxicity. For instance, the use of nanomedicine loaded with anti-PD-1 antibodies has been demonstrated to enhance antitumor T cell responses when compared to systemic administration of the antibodies alone 76 . Nanomedicine encapsulating IL-2 has also shown increased T cell activation and proliferation within the TME 77 . Nanomedicine can also be utilized to activate and expand tumor-specific T cells directly. Nanomedicine that is coated with tumor antigens and T cell stimulatory molecules, such as anti-CD3 and anti-CD28 antibodies, have been effective in expanding functional, tumor-reactive T cells ex vivo for adoptive cell therapy 78 . Furthermore, nanomedicine that delivers agents stimulating antigen-presenting cells, like toll-like receptor agonists, can boost the priming and expansion of tumor-specific T cells within the TME 79 .

Nanomedicine also has the capacity to modulate intracellular signaling pathways that govern T-cell function. Nanomedicine encapsulating small molecule inhibitors or small interfering RNA (siRNA) aimed at key signaling nodes, including the PI3K/Akt pathway or the STAT family of transcription factors, have shown promise in enhancing T cell effector functions and potentially reversing T cell exhaustion in the TME 80 . Additionally, nanomaterials can act as tools for in vivo monitoring and imaging of T cell responses within the TME. Nanomedicine conjugated with fluorescent or radiolabeled probes have been employed to track T cell trafficking, infiltration, and activation status in both preclinical and clinical studies 81 . This capability can provide valuable insights into the dynamic interactions between T cells and the TME, and guide the optimization of nanomedicine-based immunotherapies.

Interaction with B cells

The strategic engineering of nanomedicine allows for the selective delivery of immunomodulatory agents to tumor-infiltrating B cells. For instance, nanomedicine that is loaded with siRNA directed against the transcription factor Blimp-1, a pivotal regulator in plasma cell differentiation, has been demonstrated to suppress the immunosuppressive functions of tumor-associated plasma cells 79 . Furthermore, the encapsulation of CD40 receptor agonists within nanomedicine has been utilized to augment the antigen-presenting and tumoricidal activities of tumor-infiltrating B cells 82 . Nanomedicine can also induce tumor-specific antibody responses; nanomedicine displaying tumor-associated antigens has effectively primed and activated antigen-specific B cells, culminating in the generation of antibodies that target tumors 81 . These antibodies are capable of mediating ADCC or complement-dependent cytotoxicity against tumor cells within the TME 83 . Mirroring the tactics applied to T cells, nanomedicine can modulate the intracellular signaling pathways that govern B cell function. For example, nanomedicine encapsulating inhibitors of the PI3K/Akt pathway have been shown to boost antitumor antibody production by tumor-infiltrating B cells 80 . Additionally, the delivery of siRNA targeting the transcription factor BCL-6 via nanomedicine can foster the differentiation of tumor-infiltrating B cells into plasma cells, thereby amplifying the production of tumor-specific antibodies 84 .

Interaction with NK cells

NK cells are a critical component of the immune system that can identify and eliminate cancer cells. The interaction of NK cells with nanomedicine has emerged as a promising strategy for cancer immunotherapy. Cationic nanoparticles (cNPs), for instance, have been shown to activate NK cells, enhancing their cytotoxic activity against triple-negative breast cancer cells both in vitro and in vivo . This activation was achieved without the need for genetic engineering or cytokine treatment, presenting a significant advantage over conventional methods. The cNPs altered the expression of chemokine receptors CCR4 and CXCR4 on NK cells, which are crucial for their migration towards tumor sites. Furthermore, cNP-treated NK cells could be effectively tracked in vivo using magnetic resonance imaging, highlighting the potential of this approach in monitoring the therapeutic efficacy of NK cell-based cancer immunotherapy 85 .

In addition to activation, nanomedicine can be engineered to enhance the chemotropism of NK cells, improving their migration toward tumor sites. This can be achieved by overexpressing chemokine receptors such as CXCR2 on NK cells, which has been shown to promote infiltration into lung metastases in vivo . The use of CRISPR/Cas9 technology to upregulate the expression of chemokine receptors like CXCR2 and IL-2 on NK cells has also proven effective in enhancing migration to tumor sites and improving cell killing in preclinical colon cancer models 86 .

Innovative approaches, such as the development of chimeric antigen receptors (CARs) for NK cells, have opened new avenues for the precise targeting of tumor cells. These CAR-NK cells, armed with receptors that recognize specific tumor-associated antigens, have shown remarkable potential in eliminating cancer cells both in vitro and in vivo . Furthermore, the incorporation of NK cell receptor domains into CAR constructs has been explored to improve NK cell activation and cytotoxicity 87 , 88 .

Interaction with TAMs

TAMs are instrumental in fostering an immunosuppressive microenvironment. Nanomedicine has been engineered to selectively deplete TAMs, curb their recruitment, activate macrophage-mediated phagocytosis of tumor cells, and reprogram their phenotype from the immunosuppressive M2-like to the pro-inflammatory M1-like. Such interventions can attenuate the supportive role of TAMs in tumor growth and metastasis. For instance, clodronate-loaded liposomes can selectively deplete macrophages, including TAMs, by inducing apoptosis 89 . This strategy has been demonstrated to reduce tumor growth across various cancer models. Nanomedicine that targets the CD47–SIRP α interaction can augment macrophage-mediated phagocytosis of tumor cells. Given that CD47 is frequently overexpressed on cancer cells, acting as a "don't eat me" signal, blocking this pathway with nanomedicine can facilitate the clearance of tumor cells by TAMs 90 . Inhibiting the recruitment of TAMs to the TME can significantly reduce their pro-tumorigenic effects. Nanomedicines can interfere with the signaling pathways and chemokines responsible for TAM recruitment. The CCL2/CCR2 signaling pathway is crucial for the recruitment of monocytes and their differentiation into TAMs. Nanoparticles loaded with CCR2 antagonists or siRNA can effectively reduce TAM recruitment 53 , 91 . CSF-1 and its receptor (CSF-1R) are vital for the survival and recruitment of TAMs. Nanoparticles delivering CSF-1R inhibitors can block this pathway and decrease the infiltration of TAMs into tumors 92 , 93 . PEGylated gold nanoparticles functionalized with M2pep to deliver sulfated anti-VEGF siRNA have been utilized to target and inhibit the recruitment of immunosuppressive M2-type macrophages 94 ( Fig. 3 ). M2-targeting nanoparticles loaded with siRNA against the CSF-1R receptor and the α -M2pep fusion peptide serve a similar function. The CSF-1R siRNA specifically suppresses M2-like macrophage recruitment, while the α -M2pep enhances nanoparticle binding and uptake by this TAM subpopulation. Importantly, siRNA-carrying M2NPs have down-regulated the expression of exhaustion markers (PD-1 and Tim-3) on infiltrating CD8 + T cells and stimulated their IFN- γ secretion, indicating a restoration of T cell immune function 95 . As previously mentioned, the CD47–SIRP α interaction inhibits macrophage phagocytosis of tumor cells. Nanoparticles designed to block this pathway can "turn on" macrophage-mediated engulfment of tumor cells, promoting their clearance. Studies have shown that anti-CD47 antibody-conjugated nanoparticles can significantly enhance macrophage phagocytosis both in vitro and in vivo 90 , 96 . Nanoparticles can also be functionalized with opsonins, such as IgG antibodies, that bind to tumor cells and mark them for phagocytosis, aiding in the recognition and destruction of tumor cells by macrophages 97 . Engineered nanoparticles coated with tumor-specific antibodies can further promote the recognition and engulfment of tumor cells by TAMs 98 . Figure 3 RNAi-M2pep-AuNPs hinder lung cancer progression by silencing tumor-associated macrophages and cancer cells. (A) Gold nanoparticles (AuNPs, ≈15 nm) functionalized with thiolated-PEG-COOH conjugated to TAMs-targeting peptide (M2pep) and thiolated anti-VEGF siRNA labeled with Alexa Fluor 488. (B) Schematic of the outcome of the proposed combined silencing therapy (immunotherapy targeting TAMs and cancer cells) in vivo via highly specific and potent nanoparticles administered directly to bronchial airways. (C) Representative light microscopy images of BAL cells, specifically murine macrophages recovered from bronchoalveolar lavage illustrating cells from mice treated with RNAi- and RNAi-M2pep-AuNPs (0.05 mg/kg of siRNA) for days 1, 7, and 14. Black spots on macrophages treated with only RNAi-M2pep-AuNPs represent internalized NPs. Scale bars: 15 μm. (D) Immunofluorescence microscopy images of recovered macrophages from BAL fluid show RNAi-M2pep-AuNPs (green) internalization and VEGF (red) expression during 14 d of exposure. Nuclei are stained with DAPI (blue). Scale bars: 10 μm. These pictures are a composite of stylized images captured with a confocal microscope. (E) Live imaging of BALB/c nude mice bearing A549-luciferase-C8 human lung adenocarcinoma tumors nontreated (Sham) and treated with both RNAi- and RNAi-M2pep-AuNPs and with RNAicontrol-M2pep-AuNPs (dose of 0.05 mg/kg of siRNA). Representative imaging of individual mice from each treated group ( n = 6 animals) is shown at days 18 and 36. (F) Bioluminescence and epi-fluorescence analysis of ex vivo lungs from nontreated and treated mice. (G) Relative tumor size in BALB/c nude mice bearing lung tumor xenografts treated with the RNAi- and RNAi-M2pep-AuNPs, compared to untreated mice (sham), RNAicontrol-AuNPs, and RNAicontrol-M2Pep-AuNPs. The mice were treated through repeated intratracheal instillation at 0.05 mg/kg of siRNA on Days 14, 18, and 21. The tumor volume was monitored by luciferase bioluminescence ( n = 6, ∗ P < 0.05, ∗∗∗ P < 0.005). Reprinted with the permission from Ref. 94 . Copyright © 2015 Wiley. Figure 3

Reprogramming TAMs from a pro-tumorigenic (M2-like) phenotype to an anti-tumorigenic (M1-like) phenotype can significantly bolster anti-tumor immunity. Certain cytokines and small molecules can reprogram TAMs to an M1-like phenotype, and nanoparticles can be engineered to deliver these agents directly to TAMs within the TME. For example, nanoparticles loaded with IFN- γ or TLR agonists have been shown to shift TAMs towards a pro-inflammatory, tumoricidal phenotype (M1) 99 . CRISPR/Cas9-loaded nanoparticles can target and edit specific genes within TAMs to reprogram their function. Knocking out genes that promote the M2 phenotype or upregulating genes associated with the M1 phenotype can effectively reprogram TAMs 100 .

Iron-oxide nanoparticles, such as ferumoxytol, can promote the repolarization of immunosuppressive M2 macrophages towards a pro-inflammatory M1 phenotype. This transition is driven by the iron-mediated Fenton reaction, inducing ROS production and tumor cell apoptosis. Notably, the apoptotic tumor cells further stimulate M1 polarization, creating a feedback loop that increases TNF- α and nitric oxide levels. Administration of iron-oxide nanoparticles has also been correlated with elevated M1-associated markers like TNF- α and CD86, as well as decreased M2 markers such as CD206 and IL-10 101 . Additionally, Fe 3 O 4 /MPs-CpG/liposomes and NK membrane-shrouded photosensitizer-loaded nanoparticles have been reported to repolarize M2 phenotypes to M1 phenotypes. Researchers have developed a modified albumin nanoparticle platform functionalized with two ligands, transferrin receptor-binding peptide and mannose. This platform was used to co-deliver the disulfiram/copper complex and regorafenib, efficiently suppressing cancer cell growth and successfully repolarizing immunosuppressive M2 macrophages towards a pro-inflammatory M1 phenotype 102 .

Interaction with MDSCs

MDSCs constitute a heterogeneous group of immune cells that are pivotal in tumor-induced immunosuppression. Nanoparticles provide a variety of mechanisms to engage with MDSCs and modulate their functionality within the TIME. The capacity to deliver immunomodulatory agents, regulate recruitment and function, promote differentiation, modulate metabolic activity, and inhibit immunosuppressive factors is of significant importance for bolstering anti-tumor immune responses. For example, a formulation of nanoparticles combining low-molecular-weight heparin and tocopherol succinate has been developed to target adhesion molecules essential for vasomotion during MDSC recruitment. These nanoparticles employ a dual mechanism: the hydrophilic end containing low-molecular-weight heparin interferes with the binding of granulocytic MDSCs (G-MDSCs) to vascular endothelial cells, impeding their penetration and adhesion to blood vessels, while the hydrophobic end with α -tocopheryl succinate (TOS) suppresses MMP-9 expression in G-MDSCs, thereby hindering the remodeling of the tumor immune microenvironment 103 . Nano-cur, formed from curcumin coupled to an FFE-ss-EE peptide, downregulates ARG1 and iNOS expression, and inhibits ROS production and IL-10 release, thus suppressing MDSC recruitment and differentiation in the TIME 104 . Given that MDSC recruitment is governed by multiple signaling axes, targeting a single receptor or cytokine often yields limited effects. Strategies that broadly adsorb MDSC-related cytokines or remodel the tumor immune microenvironment, such as employing bionic sponges 105 or platelet membrane-coated nanoparticles 106 , can effectively inhibit MDSC accumulation and enhance antitumor immunity. These approaches aim to disrupt the diverse ligand–receptor interactions that facilitate MDSC recruitment and create an unfavorable microenvironment for MDSC infiltration.

SCM-HPAD NPs, which have a core of DOX/HPAD polymer and are coated with cancer cell membranes, can deplete MDSCs more effectively than free DOX, while also reducing drug dosage, toxicity, and production costs 107 . DS@HLipo is a liposomal nanoparticle encapsulating DOX nanoparticles and free sunitinib, which rapidly releases sunitinib upon near-infrared light exposure to target tumor vasculature and MDSCs, followed by the release of DOX-NPs to eliminate tumor cells 108 . SUNb-PM is a sunitinib-encapsulated polymeric micellar nano delivery system that diminishes MDSC infiltration and induces tumor cell apoptosis 109 . High-density lipoprotein (HDL) nanoparticles, designed to mimic the properties of natural HDL, bind more effectively to the highly expressed B-1 scavenger receptor (SCARB1) on MDSCs. This binding effectively reduces the expression of ARG1, NOS2, and CCL5 in MDSCs, thereby activating the adaptive antitumor immune response 110 .

All- trans retinoic acid (ATRA) suppresses retinoic acid signaling and promotes glutathione (GSH) accumulation in MDSCs, reducing ROS expression and stimulating MDSC differentiation into mature myeloid cells. Clinical trials have evaluated ATRA in combination with chemotherapy or immunotherapy to reverse the immunosuppressive TIME. Biodegradable hollow mesoporous silica nanoparticles coated with a lipid bilayer (dHMLB) can simultaneously deliver DOX, ATRA, and IL-2, depleting immune-suppressing cells and activating immune effector cells 111 . The iNCVs (R848) are biodegradable silica nanoparticles coated with a lipid bilayer, loaded with the TLR7/8 agonist R848 and the drug doxorubicin. The primary function of iNCVs (R848) is to remodel the TME by converting immunosuppressive MDSCs into antigen-presenting cells, thereby reducing tumor immunosuppression 112 .

Interaction with Tregs

Tregs are a subset of immune cells that play a crucial role in maintaining immune homeostasis and suppressing excessive immune responses. However, their accumulation and immunosuppressive function within the TME can hinder anti-tumor immune responses. The interaction with nanoparticles within the TME can be manipulated to disrupt this suppression. They are able to deliver immunomodulatory agents, regulate recruitment and function, modulate metabolism, and inhibit immunosuppressive factors. Biomimetic nanoparticles that mimic the behavior of Tregs have been developed, which can directly interact with overactive immune cells, inhibiting their activation and reducing the immunosuppressive effects within the TME.

Indiscriminate systemic depletion of Tregs in cancer immunotherapy can increase the risk of autoimmune-related toxicity. Nanotechnology can help increase the specificity of Treg targeting in the TME to reduce side effects. The researchers utilized bare gold nanoparticles generated by laser ablation as carriers, and functionalized them with locked nucleic acid (LNA) oligonucleotides and nuclear localization signal (NLS) peptides to achieve efficient siRNA delivery into murine Tregs. This AuNP-LNA-NLS conjugate was able to effectively enter Tregs and suppress eGFP expression by up to 50% in Foxp3-eGFP transgenic mice 113 . A charge-reversible polymeric nanomodulator (SP DMC N) was designed to release a PP2A inhibitor (DMC) selectively in the acidic TME, downregulating FoxP3 to reduce Tregs and increase the CTL/Treg ratio 114 . A bivalent aptamer-peptide (AptCD28-P60) targeting CD28 on Tregs was used to improve the specificity and efficacy of a FoxP3 inhibitor peptide, enhancing tumor immunity when combined with a tumor vaccine 115 .

Interaction with non-cellular components

Nanomedicine's interaction with the TIM extends beyond cellular components, significantly impacting non-cellular elements such as the ECM and various signaling molecules. The ECM's physical properties, including its density and stiffness, can be altered by nanomedicine, facilitating immune cell behavior and trafficking. For instance, nanoparticles have been shown to disrupt the ECM and enhance the penetration of therapeutic agents into the tumor 116 .

Moreover, nanomedicine can interact with signaling molecules like cytokines and chemokines, affecting immune cell signaling pathways and reshaping the TIM to foster a more conducive environment for immune responses against cancer cells. Research indicates that nanoparticles can be engineered to respond to the tumor immune microenvironment, releasing immunomodulatory agents to counteract immunosuppressive factors such as transforming growth factor-beta (TGF- β ) and reducing tumor-associated fibroblast (TAF) activity, thereby enhancing the efficacy of immunotherapies 117 .

Furthermore, nanomedicine has the potential to act as a bridge between cellular and non-cellular elements within the TIM. By integrating the complex signaling network, it offers a more comprehensive approach to cancer immunotherapy. This includes the development of strategies that target both the tumor cells and the surrounding ECM, as well as the modulation of immune cell activity, creating a synergistic effect that can improve the efficacy of immunotherapies 118 .

Immunotherapy trials targeting tumor immune microenvironment

Targeting T cells

The therapeutic potential of T cells in immunotherapy is under intense investigation, with a focus on modulating the TME. ADP-A2M4, a novel agent, is designed to enhance T cell targeting of tumor cells by countering the TME's immunosuppressive mechanisms, particularly in advanced synovial sarcoma or myxoid/round cell liposarcoma, in conjunction with lymphodepleting chemotherapy 119 . Another strategy employs blinatumomab (BLINCYTO), a bispecific antibody that simultaneously binds to CD19 on B cells and CD3 on T cells, redirecting T cell-mediated cytotoxicity towards B cell-positive malignancies. This drug has been used in relapsed/refractory B-ALL and MRD + B-ALL, with trials indicating its potential to improve outcomes in these conditions 120 . Cibisatamab, a CEA-CD3 bispecific antibody, is being tested clinically, either as a single agent or combined with obinutuzumab, for advanced CEA-positive solid tumors. This precision medicine approach utilizes the specificity of T cells to target and eliminate CEA-expressing tumor cells, offering a tailored therapeutic strategy for certain solid tumors 121 . IGM-2323, a CD20 x CD3 bispecific DART molecule, is being evaluated in a phase I study for its safety, tolerability, and preliminary signs of antitumor activity in patients with relapsed or refractory B cell malignancies 122 . This innovative approach aims to harness the natural killing ability of T cells while minimizing off-target effects.

In the quest to augment the therapeutic potency of immunotherapy and concurrently attenuate its adverse effects, a multitude of clinical trials have been initiated, with a particular emphasis on the modulation of T cell activity within the tumor immune microenvironment. One such investigational agent is AMG 424, which is currently under scrutiny as a monotherapy for patients with relapsed or refractory multiple myeloma. This clinical study, launched in 2019, endeavors to elucidate the safety profile and therapeutic efficacy of AMG 424 within this specific patient cohort 123 . MGD024, a CD123 x CD3 bispecific DART molecule, is also under evaluation in a phase I clinical trial for patients with relapsed or refractory CD123-positive hematologic malignancies, which began in 2022. The trial is assessing the safety, tolerability, and early anti-neoplastic activity of MGD024 124 . PRS-343, engaging HER2 and 4–1BB, is the subject of a phase I clinical trial for patients with HER2-positive malignancies, which started in 2019. This trial is conducting a thorough assessment of various therapeutic indicators relevant to PRS-343's potential 125 . For a comprehensive overview of clinical trials targeting the tumor immune microenvironment, refer to Table 1 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 . These trials exemplify the diverse strategies being explored to harness T cells for cancer immunotherapy, reflecting the dynamic and evolving landscape of cancer treatment. Table 1 Clinical trials of drugs targeting the tumor immune microenvironment. Table 1 Target Mechanism Drug Strategy (combination drugs) Conditions Phase Year Identifier Ref T Cells Improving tumour targeting ADP-A2M4 Lymphodepleting chemotherapy (fludarabine and cyclophosphamide) Advanced synovial sarcoma or MRCLS II 2024 NCT03132922 119 Blinatumomab (BLINCYTO) Chemotherapy Relapsed/refractory B-ALL; MRD + B-ALL III 2023 NCT02101853 120 Cibisatamab Single agent with or without obinutuzumab Advanced CEA-positive solid tumors I 2024 NCT02324257 121 IGM-2323 Single agent Relapsed or refractory FL, DLBCL, MZL I 2023 NCT04082936 122 Restricting T cell stimulation to mitigate adverse effects. AMG 424 Single agent Relapsed or refractory multiple myeloma I 2019 NCT03445663 123 MGD024 Single agent Relapsed or refractory CD123-positive hematologic malignancies I 2022 NCT05362773 124 PRS-343 Single agent Solid tumors (gastric, breast, gynecological, colorectal, gallbladder, bladder, pancreatic, salivary duct, melanoma) I 2019 NCT03330561 125 B Cells Inhibit B cell activity Idelalisib Combined rituximab (for CLL) Relapsed CLL; relapsed follicular B-cell NHL; relapsed SLL III 2017 NCT01659021 129 Relieve the inhibitory effect on lymphocytes Icatolimab (TAB004/JS004) Toripalimab Advanced unresectable solid tumour; Metastatic solid tumour I 2022 NCT04137900 128 Belzutifan (MK-6482, PT2977) Single agent Renal cell carcinoma, CNS hemangioblastomas, pancreatic neuroendocrine tumors associated with VHL disease II 2021 NCT03401788 127 Crizotinib Single agent Haematologic cancers; solid tumours; Metastatic cancer II 2024 NCT02034981 126 NK cells Engaging NK cells via one activating receptor AFM28 Single agent Relapsed/Refractory AML I 2022 NCT05817058 133 AFM24 Combination with atezolizumab Advanced EGFR-expressing solid tumors I/II 2024 NCT04259450 132 Engaging NK cells via two activating receptors DF1001 Single agent Advanced solid tumors, at least HER2 1+ expressing tumors I/II 2023 NCT04143711 131 SAR445514(IPH64) Single agent Relapsed/refractory multiple myeloma and relapsed/refractory light chain amyloidosis I/II 2023 NCT05839626 130 TAMs Inhibit recruitment Carlumab/CNTO 888 (anti-CCL2 antibody) Combined chemotherapy (docetaxel/gemcitabine/Paclitaxel and carboplatin/DOXIL®/Caelyx® doxorubicin HCL liposome injection) Solid tumors I 2015 NCT01204996 149 PF-04136309 (CCR2 antagonist) Combined chemotherapy (Oxaliplatin/Irinotecan/Leucovorin/Fluorouracil) Pancreatic neoplasms I 2016 NCT01413022 137 Maraviroc (CCR5 antagonist) Combined immunotherapy (Pembrolizumab) Metastatic colorectal cancer I 2022 NCT03274804 157 Deplete and suppress TAMs Pexidartinib/PLX3397 (CSF-1R inhibitor) Monotherapy PVNS or GCT-TS III 2019 NCT02371369 135 ARRY-382 (CSF-1R inhibitor) Combined immunotherapy (Pembrolizumab) Advanced solid tumors II 2022 NCT02880371 156 Lacnotuzumab (MCS110) Combined immunotherapy (Spartalizumab, PDR001) Solid tumors I/II 2024 NCT02807844 145 PY314 (anti-TREM2 mab) Combined immunotherapy (Pembrolizumab) Advanced renal cell carcinoma I 2024 NCT04691375 141 Reprogramming TAM function AVB-S6-500 (GAS6-AXL signaling pathway inhibitor) Combined chemotherapy (Pegylated liposomal doxorubicin/Paclitaxel) Ovarian cancer I 2021 NCT03639246 155 R484/Resiquimod (TLR7/8 agonist) Monotherapy CTCL I/II 2015 NCT01676831 147 Olaparib (PARP inhibitor) Combined immunotherapy (Durvalumab) and angiogenesis (Cediranib) Advanced leiomyosarcoma II 2023 NCT03851614 144 ONCOS-102 (expressing GM-CSF) Combination therapy with oncolytic virus and chemotherapy (Pemetrexed) Malignant pleural mesothelioma II 2023 NCT02879669 143 Block immune checkpoints Magrolimab/Hu5F9-G4 (anti-CD47 mab) Monotherapy Hematological malignancies I 2023 NCT04778397 154 Monotherapy Solid tumor I 2019 NCT02216409 134 Combined immunotherapy and Chemotherapy (Rituximab/Rituximab + Gemcitabine) B-cell non-Hodgkin's lymphoma I/II 2018 NCT02953509 136 Bintrafusp alfa Bifunctional fusion protein therapy (anti TGF- β and PD-L1) Non-small cell lung cancer I 2024 NCT02517398 142 MDSCs Inhibit recruitment AZD5069 (CXCR2 inhibitor) Combined enzalutamide Metastatic castration resistant prostate cancer I/II 2023 NCT03177187 148 BL-8040 (CXCR4 antagonists) Combined immunotherapy (Pembrolizumab) Metastatic pancreatic cancer II 2021 NCT02826486 150 , 153 Deplete MDSCs Tadalafil (ATRA) Combined cancer vaccine Head and neck cancer I 2014 NCT02544880 146 Entinostat (hdaci) Combined immunotherapy (Pembrolizumab) MDS or AML I 2024 NCT02936752 140 Reprogramming TAM function VT1021 (TSP-1 activator) Monotherapy Advanced solid tumors I 2024 NCT03364400 139 Tregs Targeting recruitment factors Mogamulizumab(Anti-CCR84 antibody) Combined immunotherapy (Nivolumab) Solid tumor I 2019 NCT02476123 152 Targeting immune checkpoints Tiragolumab (Anti-TIGIT mab) Combined immunotherapy (Atezolizumab) Non-small cell lung cancer II 2022 NCT03563716 151 Deplete Tregs Mogamulizumab (Anti-CCR4 igg1 antibody) Monotherapy Advanced solid tumors CCR4-negative I 2023 NCT01929486 138 TAMs, tumor-associated macrophages; MDS, myelodysplastic syndromes/neoplasms; AML, acute myeloid leukemia; MRCLS, myxoid/round cell liposarcoma; B-ALL, B-cell acute lymphoblastic leukemia; MRD, minimal residual disease; CEA, carcinoembryonic antigen; FL, follicular lymphoma; DLBCL, diffuse large B-cell lymphoma; MZL, marginal zone lymphoma; CLL, chronic lymphocytic leukemia; NHL, non-hodgkin's lymphoma; SLL, small lymphocytic lymphoma; CNS, central nervous system; VHL, Von Hippel-Lindau; EGFR, epidermal growth factor receptor; CCL2, C–C motif chemokine ligand 2; CCR2, chemokine receptor 2; CSF-1R, colony-stimulating factor 1 receptor; PVNS, pigmented villonodular synovitis; GCT-TS, tenosynovial giant cell tumor of the tendon sheath; TREM2, triggering receptor expressed on myeloid cells 2; GAS6, growth arrest-specific 6; TLR7/8, toll-like receptor 7/8; CTCL, cutaneous T-cell lymphoma; PARP, poly(ADP-ribose) polymerase; GM-CSF, granulocyte-macrophage colony-stimulating factor; anti-CD47 mAb, anti-CD47 monoclonal antibody; B-cell NHL, B-cell non-hodgkin's lymphoma; CXCR2, C–X–C motif chemokine receptor 2; CXCR4, C–X–C motif chemokine receptor 4; ATRA, all- trans retinoic acid; PDE-5, phosphodiesterase type 5; MDSCs, myeloid-derived suppressor cells; HDACi, histone deacetylase inhibitor; TSP-1, thrombospondin-1; Anti-CCR4, IgG1 antibody anti-C–C chemokine receptor 4 immunoglobulin G1 antibody; Anti-TIGIT mab, anti-t cell immunoreceptor with IG and ITIM domains monoclonal antibody.

Targeting B cells

Targeting B cells has emerged as a pivotal strategy in cancer immunotherapy, with clinical trials focusing on inhibiting their activity or relieving their inhibitory effects on lymphocytes. Idelalisib, a potent PI3K δ inhibitor, has been investigated in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia (CLL), follicular B-cell NHL, and small lymphocytic lymphoma (SLL), demonstrating its efficacy in a phase II study conducted in 2017 129 .

Icatolimab (TAB004/JS004), a novel anti-BTLA antibody, is being assessed for its capacity to relieve the inhibitory effects on lymphocytes in advanced unresectable or metastatic solid tumors. The drug has been combined with toripalimab, a PD-1 inhibitor, in a phase I clinical trial initiated in 2022 128 . Belzutifan (MK-6482, PT2977), a HIF-2 α inhibitor, has shown promise as a single agent in treating renal cell carcinoma, CNS hemangioblastomas, and pancreatic neuroendocrine tumors associated with von Hippel-Lindau (VHL) disease. This drug is currently in a phase II study that started in 2021, further exploring its potential in cancer treatment 127 . Crizotinib, a kinase inhibitor targeting ALK, ROS1, and MET, is being studied as a single agent for the treatment of hematologic cancers, solid tumors, and metastatic cancer. The phase II trial, which began in 2024, aims to evaluate the drug's effectiveness in these conditions 126 .

Targeting NK cells

Natural killer (NK) cells are critical components of the innate immune system, capable of identifying and eliminating cancer cells without prior sensitization. The targeting of NK cells in the TME has become a promising strategy in immunotherapy. Several clinical trials are underway to explore the potential of engaging NK cells via different mechanisms to enhance their antitumor activity. AFM28, a bispecific antibody, is being investigated as a single agent for the treatment of relapsed/refractory acute myeloid leukemia (AML). This therapy aims to harness the power of NK cells by engaging them with CD123-expressing targets, a strategy that is currently in phase I of clinical development, with studies initiated in 2022 133 . Similarly, AFM24 is being explored in combination with atezolizumab, an anti-PD-L1 antibody, for the treatment of advanced EGFR-expressing solid tumors. This approach seeks to leverage the cytotoxic potential of NK cells while overcoming the immunosuppressive TME, and the trial is in phase I/II, as of 2024 132 . DF1001 represents a novel tri-specific NK cell engager therapy that targets HER2-expressing tumors. This therapy is designed to redirect NK cells to cancer cells, enhancing their cytotoxic effects. The phase I/II clinical trial of DF1001 is focused on patients with advanced solid tumors that express at least HER2 1 + , with the trial initiated in 2023 131 . SAR445514, another bispecific antibody, is under investigation for its safety and efficacy in patients with relapsed/refractory multiple myeloma (RRMM) and relapsed/refractory light chain amyloidosis (RRLCA). This therapy is being evaluated as a single agent and in combination with pembrolizumab, an anti-PD-1 therapy, for patients with advanced solid tumors, including those with head and neck squamous cell carcinoma, non-small cell lung cancer, and renal cell carcinoma. The trial is in phase 1/2 and was initiated in 2023 130 .

Targeting TAMs

In the TIM, tumor-associated macrophages (TAMs) are key factors affecting tumor growth and the response to immunotherapy. Recent clinical trials have focused on studying various strategies to target TAMs to enhance immune responses and therapeutic efficacy.

Initially, the recruitment of TAMs was inhibited using the anti-CCL2 antibody Carlumab/CNTO 888, in combination with multiple chemotherapy drugs such as docetaxel, gemcitabine, and paclitaxel 149 . Additionally, the CCR2 antagonist PF-04136309, when combined with chemotherapy drugs oxaliplatin, irinotecan, leucovorin, and fluorouracil, showed potential in a phase I clinical trial for pancreatic neoplasms in 2016 137 . Maraviroc, as a CCR5 antagonist, was initiated in a clinical trial in 2022 in combination with Pembrolizumab for metastatic colorectal cancer 157 .

Beyond inhibiting TAM recruitment, clinical trials are also exploring how to deplete and suppress TAMs. For instance, the CSF-1R inhibitor Pexidartinib/PLX3397, as a monotherapy, entered a phase III clinical trial for tenosynovial giant cell tumor or related lesions in 2019 135 . ARRY-382, another CSF-1R inhibitor, entered a phase II clinical trial in 2022 in combination with Pembrolizumab for advanced solid tumors 156 .

Reprogramming the function of TAMs is also a hot topic of current research. The GAS6-AXL signaling pathway inhibitor AVB-S6-500, when used in combination with chemotherapy drugs, showed promise in a clinical trial for ovarian cancer 155 . Furthermore, the TLR7/8 agonist R484, Resiquimod, as a monotherapy, entered phases I and II of a clinical trial for cutaneous T-cell lymphoma in 2015 147 . Using the " β -Elemene@Stanene" strategy for enhancing cancer chemo-immunotherapy, researchers overcome immunosuppression and enhance the effectiveness of chemo-immunotherapy. This approach is significant as it not only demonstrates the therapeutic efficacy of STNSP-based nano drug delivery systems against immunosuppressive tumors but also establishes a versatile platform for 2D nanomaterial-mediated cancer chemo-immunotherapy 158 .

Immune checkpoint inhibitors also play a significant role in cancer therapy. Magrolimab/Hu5F9-G4, a monoclonal antibody targeting CD47, entered phase I of a clinical trial for hematological malignancies in 2023 154 . Moreover, Magrolimab is also used as a single therapy or in combination with Rituximab and Gemcitabine for the treatment of B-cell non-Hodgkin's lymphoma in clinical trials 136 . Bintrafusp alfa, as a bifunctional fusion protein targeting TGF- β and PD-L1, has demonstrated potential in the second-line treatment of non-small cell lung cancer 142 .

Targeting MDSCs

Myeloid-derived suppressor cells (MDSCs) play a significant role in the TME by inhibiting the immune response against cancer. Various strategies are being explored to target MDSCs and enhance the efficacy of immunotherapy. One approach to inhibit the recruitment of MDSCs is the use of AZD5069, a CXCR2 inhibitor, which is being studied in combination with enzalutamide for metastatic castration-resistant prostate cancer (mCRPC). This clinical trial is in phase I/II and was initiated in 2023 148 . Another strategy involves the use of BL-8040, a CXCR4 antagonist, which is being combined with pembrolizumab, an anti-PD-1 therapy, for the treatment of metastatic pancreatic cancer. This trial is in phase II and began in 2021 150 , 153 . To deplete MDSCs, Tadalafil, also known as ATRA, is being investigated in combination with a cancer vaccine for head and neck cancer. This phase I trial started in 2014 146 . Entinostat, a histone deacetylase inhibitor (HDACi), is being explored in combination with pembrolizumab for the treatment of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This phase I trial was initiated in 2024 140 . Lastly, the reprogramming of MDSCs is being targeted with VT1021, a TSP-1 activator, which is being used as a monotherapy for advanced solid tumors. This phase I trial started in 2024 139 .

Targeting Tregs

Regulatory T cells (Tregs) are a subset of T cells that play a critical role in maintaining immune tolerance and suppressing excessive immune responses, including those against tumors. Targeting Tregs has emerged as a promising strategy to enhance the efficacy of cancer immunotherapy. One approach to target Tregs involves the use of mogamulizumab, an anti-CCR8 antibody, which is being investigated in combination with nivolumab, an immune checkpoint inhibitor, for the treatment of solid tumors. This clinical trial is in phase I and was initiated in 2019 152 . Another strategy aims to target immune checkpoints by using tiragolumab, an anti-TIGIT monoclonal antibody, in combination with atezolizumab for non-small cell lung cancer. This trial is in phase II and began in 2022 151 . Depletion of Tregs is also being explored as a therapeutic approach. Mogamulizumab, an anti-CCR4 IgG1 antibody, is being studied as a monotherapy for advanced solid tumors that are CCR4-negative. This phase I trial started in 2023 138 . Published clinical trials for cancer nanoparticles are shown in Table 2 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 . Table 2 Published clinical trials for cancer nanoparticles. Table 2 Active component Name Ligand target Nanocarrier Payload Indication Trial registration Year Status Ref Chemotherapy Drugs Doxil NA Liposome DOX Karposi's sarcoma, ovarian cancer, multiple myeloma NA 1995 Approved by FDA 169 Daunoxome NA Liposome Daunorubicin Karposi's sarcoma NA 1996 Approved by FDA 168 Marqibo NA Liposome Vincristine Acute lymphoblastic leukemia NCT00495079 2012 Approved by FDA 159 Onivyde DNA topoisomerase I inhibitor Liposome Irinotecan Pancreatic cancer NCT00813072 2015 Approved by FDA 166 MBP-426 Transferrin receptor Liposome Oxaliplatin Gastric, oesophageal and gastro-oesophageal adenocarcinoma NCT00355888 2009 Phase I 165 Thermodox NA Liposome DOX Hepatocellular carcinoma NCT02112656 2009 Phase III 164 Genexol-PM NA Polymeric nanoparticles Paclitaxel Breast cancer and NSCLC NA 2007 Approved in South Korea 163 Opaxio NA Polymeric nanoparticles Paclitaxel Head and neck cancer; Glioblastoma NA 2012 Approved by FDA 162 Antibodies Targomirs Anti-EGFR Minicell Mir-16-based microRNA mimic NSCLC, MPM NCT02369198 2017 Phase I 178 AB160 Anti-VEGF Nab-paclitaxel Bevacizumab GUC NCT02020707 2024 Phase I 171 Antibody fragments C225-ils-DOX Anti-EGFR Fab’ Liposome DOX Solid tumors NCT01702129 2012 Phase I 177 MM-302 Anti-HER2 scfv Liposome DOX Breast cancer NCT01304797 2018 Phase I 179 SGT-53 Anti-TFR scfv Liposome P53 plasmid Solid tumors NCT00470613 2013 Phase I 175 Pancreatic cancer NCT02340117 2008 Phase II 173 SGT-94 Anti-TFR scfv Liposome RB94 plasmid GUC NCT01517464 2016 Phase I 176 Lipovaxin-MM Anti-DC-SIGN VH Liposome Melanoma antigens and IFN- γ Melanoma NCT01052142 2018 Phase I 181 Proteins MBP-426 Tf Liposome Oxaliplatin Solid tumors NCT00355888 2009 Phase I 183 AGC or EAC NCT00964080 2009 Phase I/II 182 CALAA-01 Tf Polymeric nanoparticles RRM2 siRNA Solid tumors NCT00689065 2014 Phase I 174 Peptides Mepact NA Liposome Muramyl tripeptide phosphatidyl ethanolamine Non-metastatic osteosarcoma NA 2009 Approved in Europe 167 Rexin-G Vwf-derived motif Retroviral vector Dn-CCNG1 Osteosarcoma NCT00572130 2009 Phase II 160 Dn-CCNG1 Sarcoma NCT00505713 2019 Phase I/II 180 Dn-CCNG1 Pancreatic cancer NCT00504998 2019 Phase I/II 180 Inorganic nanoparticles Aguix Radiotherapy Diethylene glycol Gadolinium Metastatic brain tumor NCT02820454 2021 Phase I 170 NBTXR3 Radiotherapy Hafnium oxide NPs Adult soft tissue sarcoma NCT01433068 2019 Approved in Europe 161 188 Re-liposome NA Liposome 188 Re 188 Re Approved in Taiwan, China. MA1101G0 2019 Phase 0 172 AGC, advanced gastric cancer; dn-CCNG1, dominant-negative mutant construct of cyclin G1; DOX, doxorubicin; EAC, esophageal adenocarcinoma; GUC, genitourinary cancers; HER2, growth factor receptor 2; MPM, malignant pleural mesothelioma; NSCLC, non-small cell lung cancer; NP, nanoparticles; Tf, transferrin; vWF, von Willebrand factor.

Role of nanomedicine in overcoming tumor immunosuppression

Inhibiting immunosuppressive cell recruitment and function

The engagement of immunosuppressive cells within the TME is a pivotal factor propelling cancer progression and impeding therapeutic efficacy. Nanomedicine presents groundbreaking methods to regulate these processes, thus amplifying the potency of cancer therapies. Inhibiting the recruitment of immunosuppressive cells can be achieved through nanoparticles that disrupt the signaling pathways guiding their migration toward tumors. For instance, nanoparticles designed to deliver siCCR2 have been effectively utilized to target inflammatory monocytes, consequently reducing their accumulation in the TME and altering the immunosuppressive milieu 184 . Another strategy encompasses the deployment of nanoparticles laden with pCCL2 LPD NP, which are directed at TAMs, suppressing the expression of tumor-associated antigens while simultaneously promoting T-cell infiltration and depleting M2 macrophages 91 .

Nanomedicine possesses the capability to target the functionality of immunosuppressive cells already entrenched within the TME. For example, M2pep/anti-VEGF siRNA nanoparticles have been crafted to specifically hone in on M2 macrophages, thereby silencing VEGF mRNA and neutralizing their immunosuppressive capabilities 94 . Along similar lines, α -M2pep/cholsiCD115 nanoparticles have been engineered for dual-targeted delivery to M2-type TAMs, enhancing the precision of therapeutic interventions 95 . Beyond inhibition, it can also modulate the phenotype of immunosuppressive cells, directing them toward a more beneficial state. For example, DOX/ α GC PLT/DOX/ α GC NPs have shown the capacity to impede the adhesion between granulocytic myeloid-derived suppressor cells (G-MDSCs) and endothelial cells, which leads to a reduction in MMP-9 expression in G-MDSCs and a subsequent compromise of their immunosuppressive activity 103 .

Depletion and suppression of immunosuppressive cells

The targeted depletion and suppression of immunosuppressive cells are essential in cancer therapy, aimed at normalizing the TME and bolstering antitumor immune responses. Nanomedicine facilitates this strategy through the development of targeted delivery systems designed to selectively eliminate or modulate the activity of these cells. ALN-BSP conjugated polymer nanoparticles have been specifically engineered to target and deplete TAMs, thereby inhibiting angiogenesis and enhancing local immune surveillance 185 . BLZ-945, a CSF-1R inhibitor, when delivered via nanocarriers, enhances the targeting of TAMs and contributes to their depletion 186 . MDSCs are immature myeloid cells that accumulate in various cancers and are pivotal in immune suppression. DSB PSNP nanoparticles simulate apoptosome-mediated phagocytosis for tumor-specific macrophage targeting, resulting in the depletion of immunosuppressive cells 187 . Additionally, DOX S-CM-HPAD NPs have been formulated to suppress the activity of MDSCs, regulate tumor immune evasion, and stimulate T-cell proliferation and cytokine production 188 .

Combination therapies targeting both tumor vascular epithelial cells and MDSCs have shown promising results. An example of this is the DOX-NP/Sunitinib DS@HLipo liposomes, which are crafted to target multiple cellular components, dismantling the immunosuppressive network and amplifying the collective antitumor defense 107 . Beyond cell depletion, the modulatory potential of MDSCs is also utilized to reduce their immunosuppressive impact. SCARB1-targeted HDL NP therapy illustrates this approach, where the activity of MDSCs is dampened, thus fostering a more favorable TME for effective immune reactions 109 .

Reprogramming immunosuppressive cells

Within the TME, macrophages can assume a spectrum of phenotypes, with M2 macrophages often manifesting immunosuppressive characteristics. The reprogramming of these cells from a suppressive to an activated state, such as the pro-inflammatory M1 phenotype, can leverage their potential in the fight against cancer. Nanomedicine plays a pivotal role in this strategy by enabling the targeted delivery of reprogramming agents that induce this phenotypic shift towards antitumor activity. For example, micelles containing Poly I:C and ZnPP have been used to reprogram TAMs by modulating the expression of ROS and STAT3, promoting a shift towards the M1 phenotype 189 . SiRNA can be employed to target specific genes that contribute to the immunosuppressive phenotype of cells. Nanoparticles, such as AS/IKK β siRNA ST-AS&Si, have been engineered to co-deliver M2-targeted IKK β siRNA and the pH-sensitive STAT6 inhibitor AS, enabling precise drug release and effectively repolarizing M2 macrophages 117 . The delivery of specific genes can also reprogram immunosuppressive cells. Nanoparticles like IRF5/IKK β mRNA NPs have been engineered to provide genes encoding master regulators of macrophage polarization, which can instruct macrophages to adopt a more antitumor phenotype 190 , 191 , 192 . Combining reprogramming agents with other therapies can enhance the overall effect. For example, liposomes such as GEF/VOR tLGV have been applied to reprogram TAMs and activate a specific signaling axis for drug-resistant non-small cell lung cancer, integrating the reprogramming effect with chemotherapeutic agents 193 . Moreover, Dendritic cells can also be reprogrammed to enhance their antigen-presenting capabilities. Nanoparticles, such as CpG ODN/anti-IL-10 ODN/anti-IL-10R ODN PDO, have been used to effectively educate macrophages without impacting systemic immunity, fostering a more robust immune response against cancer 194 .

Activating phagocytic function of immune cells

The innate ability of immune cells to engulf and neutralize tumor cells through phagocytosis is a vital component of the body's defense mechanisms against cancer. Nanomedicine can be utilized to enhance this function, thereby improving the body's innate ability to combat cancer. One approach involves the use of nanoparticles to deliver agents that can directly enhance the phagocytic activity of macrophages. Notably, recombinant CALR/aCD47 nanoparticles have demonstrated the capacity to enhance macrophage-mediated phagocytosis, thereby bolstering antitumor effectiveness 195 . CD47, a protein frequently overexpressed on cancer cells, can suppress macrophage phagocytosis by engaging with its receptor on macrophages, signal regulatory protein alpha (SIRP α ). To counteract this, nanoparticles like vSIRP α -probe have been formulated to obstruct this interaction, promoting CD47-targeted cancer visualization and stimulating anticancer immune responses reliant on phagocytosis 196 . Additionally, the concept of programming macrophages into CAR-M1 macrophages through nanocomplexes represents a groundbreaking tactic. This has been realized through the conveyance of the CAR gene MPEI/pCAR–IFN- γ , which provides macrophages with chimeric antigen receptors capable of specifically identifying and phagocytosing tumor cells 197 . Dendrimer-based proton sponge nanocomposites exemplify another avant-garde strategy. The combination of G5AcP dendrimer with Cu(II) and DOX has illustrated the potential to curb autophagy and reprogram the TME to foster macrophage activation, leading to the efficacious eradication of tumors 198 . These advancements underscore the transformative potential of nanomedicine in invigorating the phagocytic function of immune cells and, by extension, the overall immune response against cancer.

Modulating Treg function

Tregs play a critical role in preserving immune system balance, yet their abundance within the TME. can hinder the body's antitumor defenses. Nanomedicine offers sophisticated, targeted methods to influence Treg behavior, either by reinforcing their function to strengthen tumor immunity or by diminishing their suppressive effects to boost the potency of cancer therapies. Gold nanoparticle conjugates have been employed to effectively deliver nucleic acids into Tregs, thereby modulating their function and amplifying the immune response against tumors 113 . Charge-conversion polymer nanoparticles, like SPDMCN, have been crafted for improved stability and the ability to penetrate the TME more deeply. These particles are capable of releasing their cargo, dimethylchitosan (DMC), under the acidic conditions prevalent in the TME, thereby suppressing the expression of FoxP3 and reducing the immunosuppressive impact of Tregs 114 . Aptamer-peptide chimeras, such as AptCD28-P60, have been developed to improve the precision targeting of Tregs, enabling a decrease in the required dosage while simultaneously amplifying the immune response 115 . By employing these nanotechnological strategies, researchers can more effectively manage the presence and function of Tregs in the TME, tipping the scales in favor of a more robust immune response against cancer.

Combine with traditional therapies

The fusion of nanomedicine with traditional cancer therapies has shown great potential in overcoming the constraints of current therapeutic options and improving patient outcomes. This integration combines the precision of nanoscale drug delivery systems with the established efficacy of conventional treatments, creating a synergistic approach to cancer therapy. For instance, engineered platelets displaying PD-1 have been utilized to enhance cancer immunotherapy following surgery. This method leverages the immune system's ability to target any residual cancer cells that may remain after surgical intervention 199 . The application of nanoparticle-mediated hyperthermia has been employed to deplete tumor-associated Tregs, which can significantly boost the effects of ICB cancer immunotherapy. This approach can re-energize the immune system's ability to detect and destroy cancer cells 200 . The encapsulation of chemotherapeutic agents like MTO/IND within liposomes can halt cancer progression by inducing immunogenic cell death (ICD) and inhibiting the IDO-1 pathway simultaneously. This combined therapeutic strategy can trigger a robust immune response against the tumor 201 . Normalization of the tumor's acidic microenvironment through the use of nanoparticles, such as those delivering siLdha, can improve the effectiveness of traditional therapies. This is achieved by optimizing drug delivery and enhancing the functionality of immune cells 202 . Liposomes co-encapsulating Dox and alendronate can increase the sensitivity to both chemotherapy and immunotherapy by repolarizing TAMs and activating gamma-delta T lymphocytes. This dual-targeted strategy can significantly increase the overall effectiveness of cancer treatment 203 . Chimeric peptide-engineered self-delivery nanomedicines for photodynamic therapy have been developed to eradicate primary tumor growth and reprogram M2-type TAMs to the M1-type, thereby stimulating T cell-mediated antitumor immunity. This multifaceted therapeutic approach can provide substantial improvements over traditional treatments 204 .

The integration of nanomedicine with oncolytic virus-like particles has opened new avenues for enhancing tumor immunotherapy. A recent study presents an innovative approach using an ion-enhanced nanoplatform, PolyIC@ZIF-8, which not only mimics the function of an oncolytic virus by inducing tumor cell apoptosis and recruiting T cells in a tumor antigen-dependent manner but also releases Zn2 + to further enhance T cell recruitment and activation in a tumor antigen-independent manner 205 . This strategy signifies a promising direction for the development of new immunotherapies that can effectively target and eradicate tumors. The interaction between intracellular microbiota (ITM) and TME provides a new approach for tumor immunotherapy. The presence of ITM in TME can promote the delivery of antigens to tumor cells, provide cross-antigens to promote immune cells to attack tumors, and also affect the activity of immune cells and stromal cells. This type of treatment mainly works by deleting harmful bacteria, increasing beneficial bacteria, and changing microbial metabolites 59 . The innovative approach utilizing colistin crosslinked gemcitabine micelles (CCGM) presents a significant advancement in overcoming tumor drug resistance induced by intratumoral microorganisms. The study develops a co-delivery system of an antibiotic and an anticancer drug, encapsulated within micelles that are designed to release their payload in response to the tumor's microenvironment. Specifically, the CCGM is triggered by intracellular glutathione levels within the tumor to release colistin and gemcitabine, thereby inhibiting microbial growth and reversing drug resistance 206 .

Multifaceted biomimetic systems

Incorporating biomimetic systems into nanomedicine has paved innovative paths in cancer therapy. These systems harness the body's inherent mechanisms to refine treatment efficacy 207 . Biomimetic nano-RBCs, which imitate red blood cells, have shown promise in homing in on endogenous TAMs. By doing so, they reprogram the immunosuppressive TME to enhance chemo-immunotherapy. These biomimetic systems are capable of depleting M2-type TAMs and impeding their recruitment, which in turn, escalates the impact of traditional chemotherapy and immunotherapy agents 208 . The in situ generation of ROS-responsive scaffolds, embedded with therapeutic agents like gemcitabine and checkpoint inhibitors, represents an integrated therapy approach. This method utilizes biomaterials to escalate the potency of treatments. Such scaffolds can boost the tumor's immunogenic properties and increase the levels of proinflammatory cytokines, leading to a synergistic effect when paired with immunotherapy 209 . CXCR4-targeting nanocomplexes, such as FX/paclitaxel, have been designed to enhance T-cell infiltration and support antigen presentation. These nanocomplexes work to reduce the presence of MDSCs and Tregs, thereby amplifying the effectiveness of anti-PD-L1 immunotherapy 210 . The development of multifunctional redox-responsive nanoplatforms stands as an advanced biomimetic strategy. These platforms have the potential to activate both macrophages and T cells for antitumor immunotherapy. They can be customized to respond to specific stimuli within the TME, releasing their therapeutic payloads in a controlled manner to ensure maximum therapeutic benefits ( Fig. 4 ) 211 . The strategies on nanomedicine targeting the tumor immune microenvironment are shown in Table 3 91 , 94 , 95 , 103 , 104 , 105 , 107 , 108 , 109 , 110 , 113 , 114 , 115 , 117 , 158 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 . Figure 4 Strategy for reversing immunosuppression in tumor microenvironment. Nanotechnology is employed to reverse immunosuppression within the tumor microenvironment, enhancing the body's natural ability to combat cancer. This strategy involves targeting immune-suppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) with nanoparticles designed to deplete or reprogram these cells. Additionally, regulatory T cells (Tregs) are targeted to reduce their immunosuppressive effects. Multifunctional nanoparticles are used to deliver therapeutic agents that activate T cells, induce cancer cell death, and stimulate an immune response. By modulating the tumor microenvironment and enhancing immune cell function, this approach aims to overcome the immunosuppressive barriers that tumors often use to evade immune detection and destruction. Figure 4 Table 3 Strategies on nanomedicine targeting the tumor microenvironment. Table 3 Mechanism Delivery system Payload Immune niche Function Year Ref Inhibit recruitment Nanoparticle Siccr2 CNP-siRNA TAMs Increase the sensitivity of chemotherapy 2018 184 Nanoparticle Pccl2 LPD NP TAMs Suppresses TAMs, increases T-cell infiltration and decreases the population of M2 macrophages 2021 91 Nanoparticle M2pep/anti-VEGF siRNA M2 macrophages Silence VEGF mRNA in M2 macrophages and M2pep to increase its M2 TAMs targeting 2015 94 Nanoparticle Α-M2pep/cholsicd115 M2-type TAMs Dual-targeted delivery of cholinesterase CD115 to M2-type TAMs 2017 95 Nanoparticle DOX/ α GC PLT/DOX/ α GC NPs MDSCs Inhibit the adhesion between G-MDSCs and endothelial cells and reduce the expression of MMP-9 in G-MDSCs 2020 103 Nano-filament Curcumin Nano-cur MDSCs Relieve the tumor burden by regulating and improving the TME 2022 104 Nanosized sponge Pcss Neutrophils Inhibit most membrane receptors on neutrophils to neutralize MDSC-related cytokine effects 2020 105 Nanoparticle Bi2-WO6-NP PM-biw nps MDSCs Integrate radiation therapy, PTT and PDT to overcome the immunosuppression caused by MDSCs. 2020 218 Deplete and suppress immunosuppressive cell Conjugated polymer ALN-BSP TAMs Eliminates TAMs, inhibits angiogenesis, and restores local immune surveillance 2014 185 Conjugated polymer BLZ-945 TAMs Enhance targeting of the highly selective CSF-1R inhibitor BLZ-945 with nanocarriers 2017 186 Nanoparticle DSB PSNP Tumor-specific macrophages Mimics apoptosome-mediated phagocytosis for tumor-specific macrophage targeting 2020 187 Conjugated polymer DOX PAMB/DOX Macrophages Stepwise-responsive; TME hypoxia and high ROS for targeted delivery; PEG modification to reduce hepatic accumulation 2020 188 Nanoparticle DOX S-CM-HPAD NPs MDSCs Inhibit MDSCs to regulate tumor immune escape; improve T-cell proliferation and stimulate cytokine secretion to alter TME 2019 107 Liposome DOX-NP/Sunitinib DS@hlipo Tumor vascular epithelial cells and MDSCs Target multiple regions, including tumor vascular epithelial cells and MDSCs 2022 108 Micelle Sunitinib sunb-PM MDSCs Reduce MDSCs in TME and inhibit Stat3 and AKT signaling pathways to induce apoptosis in tumor cells 2017 109 Nanoparticle HDL nps SCARB1-targeted HDL NP therapy MDSCs Inhibited MDSC activity 2018 110 Reprogramming immunosuppressive cells Micelle Poly I:C Znpp PM/PIC TAMs Repolarize TAMs through modulating the expression of ROS and STAT3 2018 189 Nanoparticle AS/IKK β siRNA ST-AS&Si M2 macrophages Codelivery of M2-targeted IKK β siRNA and STAT6 inhibitor AS; pH-sensitive for precise drug release 2020 117 Nanoparticle IRF5/IKK β mRNA IRF5/IKK β mRNA nps Macrophages Provide with genes encoding master regulators of macrophage polarization. 2019 190 Liposome GEF/VOR TLGV TAMs Repolarize TAMs and trigger ROS/MSRA/EGFRT790 M axis for drug-resistant NSCLC 2017 193 Nanoparticle Cpg ODN/anti-IL-10 ODN/anti-IL-10R ODN PDO TAMs Delivery of ODN to TAMs effectively re-educated macrophages without affecting systemic immunity 2012 194 2D stanene-based nanosheets (STNSP) Β -Elemene TAMs Overcome immunosuppression and enhance chemo-immunotherapy 2023 158 Nanoparticle CpG ODNs MCMC/HA/PS/ODN NPs Macrophages Dual-targeting delivery system enhanced secretion of proinflammatory cytokines and shifted to M1 2017 222 Nanocomplex CpG ONDs GGIC Macrophages Provide synergistic photothermal and immunological effects under NIR 2014 217 Microparticles SR-B1 targeting peptide/P5091 Brain macrophages Cross the BBB and target M2 to reprogram it 2023 221 Hydrogel scaffold KN93 MRK hydrogel Tumor-associated macrophages Provide a synergistic tumor suppression effect against through reshaping TMEs. 2020 195 Injectable hydrogel PP2/R848 PR-Gel Tumor tissue Improve the drug accumulation at the tumor tissue and enable more enduring drug level 2021 216 Engineered-TAA Telratolimod telratolimod@adipcyt TAMs TAA are engineered to promote the polarization of TAMs to M1 2023 220 Milk exosome (MEXO) system 7D12-MEXO-M2pep-siPDL1 M2 macrophages Inducing reprogramming of M2-type TAMs to M1-type macrophages 2024 215 Engineered extracellular vesicles AIE-active photosensitizers Macrophages Improving tumor immunosuppressive microenvironment and overcoming immune escape through photodynamic therapy (PDT) 2024 214 Poly(2-alkyl cyanoacrylate) (PACA) nanoparticles Cabazitaxel (CBZ) Myeloid cells, especially macrophages Enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs, contributing to an inflammatory, immune activated tumor microenvironment 2024 213 Cyclodextrin-modified poly(D,L-lactide- co -glycolide) (PLGA) nanoparticles R848 TAMs Promoting M1 polarization of TAMs and enhancing the efficacy of colon cancer treatment 2024 212 Activate phagocytic function Nanoparticle Recombinant CALR/aCD47 Macrophages Enhance the phagocytosis and improved antitumor efficacy 2020 219 Activatable prob vSIRP α -probe Macrophages Facilitate CD47-targeted cancer imaging and elicit anticancer immune responses depending on phagocytosis 2020 196 Nano-complexes CAR gene MPEI/pCAR-IFN-γ Macrophages Program macrophages into CAR-M1 macrophages displaying enhanced cancer-directed phagocytosis 2021 197 Dendrimer-based proton sponge nanocomposites Proton sponge g5acp dendrimer, Cu(II), and DOX TAMs Inhibiting autophagy and reconstructing TME toward macrophage activation for effective tumor elimination 2024 198 Enhancing Treg efficiently Nanoparticle LNA/NLS AuNP-LNA-NLS Tregs Import nucleic acids into Tregs efficiently 2016 113 Nanomodulator DMC SPDMCN Tregs Charge conversion improved stability and tumor infiltration, low-pH triggered the release of DMC to inhibit FoxP3 expression 2021 114 Aptamer-peptide chimera Aptcd28-P60 Tregs Enhance targeting to reduce dose and strengthen patient immunity 2016 115 Combine with traditional therapies Engineered platelet PD-1 – Enhance cancer immunotherapy after surgery 2018 199 Nanoparticle Ionps Tregs Deplete Tregs and collaboratively enhance ICB cancer immunotherapy 2020 200 Liposome MTO/IND – Inhibit cancer progression in model mice through concurrent induction of ICD and inhibition of the Ido-1 pathway 2020 201 Nanoparticle siLdha – Normalize tumor acidic microenvironment 2019 202 Liposomes Doxorubicin (Dox) and alendronate (Ald) TAMs and gamma-delta T lymphocytes Enhance the sensitivity of chemotherapy and immunotherapy by repolarizing TAMs and activating gamma-delta T lymphocytes 2023 203 Chimeric peptide-engineered self-delivery nanomedicine Photosensitizer chlorine e6 (Ce6) and TLR7/8 agonist imiquimod (R837) TAMs Eradication of primary tumor growth through PDT, polarization of M2-type TAMs to M1-type, activation of T cell antitumor immunity 2023 204 Oncolytic virus like Polyic and Zn 2+ T Cells Induced tumor cell apoptosis; enhanced T cell-mediated antitumor response 2022 205 Nano-micelle Colistin and gemcitabine Tumor microbe Intracellular glutathione triggers the release of colistin and gemcitabine, inhibiting tumor microbe growth and eliminating drug resistance. 2022 206 More than one biomimetic system Biomimetic cell DOX/O2 V [162]@DOX TAMs Deplete M2-type TAMs and reduce the recruitment of TAMs 2021 208 Scaffold Apdl1/GEM – Boost tumor immunogenicity and upregulate expression of proinflammatory factors 2018 209 Nanocomplex FX/paclitaxel T Cells Increase T-cell infiltration; to promote antigen presentation and decrease the number of MDSCs/Tregs 2020 210 Nanoparticle Motolimod/catalase/siPD-L1 TAMs, MDSCs, T cells Combined immunotherapy targeting TAMs, MDSCs and T cells to activate both innate and adaptive immunity 2023 211 TAAs, tumor-associated antigens; M2 macrophages, M2-type tumor-associated macrophages; VEGF mRNA, vascular endothelial growth factor messenger RNA; M2pep, M2-targeting peptide; TAMs, tumor-associated macrophages; CSF-1R, colony-stimulating factor 1 receptor; ROS, reactive oxygen species; TME, tumor microenvironment; PEG, polyethylene glycol; IKK β , inhibitor of nuclear factor kappa-b kinase beta; ODN, oligodeoxynucleotide; NIR, near-infrared; BBB, blood–brain barrier; MDSCs, myeloid-derived suppressor cells; MMP-9, matrix metalloproteinase-9; PTT, photothermal therapy; PDT, photodynamic therapy; ICD, immunogenic cell death; IDO-1, indoleamine 2,3-dioxygenase 1; DOX, doxorubicin; ATRA, all- trans retinoic acid; IL-2, interleukin-2; Tregs, regulatory t cells; DMC, dimethylchitosan; FoxP3, forkhead box p3.

Future directions of nanomedicine in immunotherapy

Development of multifunctional nanoplatforms

The progression of nanomedicine is characterized by a significant trend towards the development of sophisticated multifunctional nanoplatforms, which are set to revolutionize cancer therapy 223 , 224 . These cutting-edge platforms are expected to lead a therapeutic transformation by overcoming the limitations of conventional single-agent treatments and adopting integrated systems that can perform simultaneous diagnosis, drug delivery, and therapeutic intervention. The multifunctionality of these nanoplatforms will be achieved through the strategic integration of various components, each playing a distinct role in the therapeutic sequence. For instance, the integration of imaging agents into nanoplatforms allows for the real-time tracking of therapeutic outcomes 225 , 226 . This feature empowers medical professionals to promptly assess the effectiveness of treatments and make informed decisions on patient care.

Moreover, these nanoplatforms are crafted to ensure the precise delivery of a wide range of therapeutic agents. This includes the targeted delivery of traditional chemotherapeutic agents to cancer cells, thus minimizing harm to healthy cells. Additionally, the incorporation of immune modulators is intended to strengthen the patient's immune response, enhancing its capacity to identify and combat cancer cells more effectively 211 . The targeted delivery of immune modulators could counteract the immune evasion strategies used by tumors, thereby reinforcing the body's natural defenses against cancer. Furthermore, some researchers have developed a light-triggered sequential delivery strategy that has shown great promise in multimodal cancer therapy targeting multiple aspects, including the delivery of DOX, photosensitizer porphyrin-phospholipid (PoP), and sunitinib, in distinct spatial locations within the tumor microenvironment 108 .

The emergence of theranostics

Theranostics marks a pivotal fusion of diagnostic and therapeutic modalities, ushering in a new age of personalized medicine 227 . This holistic strategy facilitates a simultaneous approach to cancer treatment and diagnosis, supplying vital data for crafting individualized patient care plans. The amalgamation of these two functionalities within NPs is a cutting-edge advancement, presenting considerable promise for the advancement of oncology care. Theranostic NPs are meticulously designed to traverse biological barriers and target tumor immune microenvironments with precision. They are capable of being laden with a range of therapeutic agents, including chemotherapy drugs, immunotherapies, or gene-editing technologies, all intended for direct delivery to cancerous cells. Simultaneously, these NPs can also be embedded with diagnostic markers that facilitate the assessment of treatment efficacy and the genetic and environmental profiling of tumors 111 , 195 .

The diagnostic component of theranostic nanoparticles often includes imaging agents that are traceable through a variety of imaging techniques such as magnetic resonance imaging (MRI) 228 , positron emission tomography (PET) 229 , or fluorescence imaging 230 . These agents provide real-time imaging of the tumor and the therapeutic agents’ distribution, thus allowing for the accurate monitoring of drug delivery and treatment results. Moreover, theranostic nanoparticles can be tailored to react to specific stimuli present in the tumor immune microenvironment. For instance, they can be engineered to discharge their therapeutic cargo upon encountering the acidic pH 231 or the hypoxic conditions characteristic of tumors 232 . This responsive drug delivery system enhances the precision and potency of the treatment while minimizing the impact on healthy tissues. A remarkable feature of theranostic nanoparticles is their ability to map the genetic makeup of tumors. By incorporating molecular probes or nucleic acid sensors, these nanoparticles are able to identify specific genetic anomalies or expression profiles within the tumor. Such insights are crucial for the selection of targeted therapeutics and the development of personalized treatment plans 233 .

Precision engineering of nanoparticles

The advancement of nanomedicine is significantly contingent upon the precision engineering of NPs, a pivotal strategy to enhance the effectiveness of cancer treatments. Central to this strategy is the meticulous optimization of NP dimensions. Nanoparticles with diameters ranging from 10 to 200 nm can effectively accumulate in tumors via the enhanced permeability and retention (EPR) effect 234 . Nonetheless, to facilitate deeper penetration into the tumor mass, smaller nanoparticles may offer benefits 235 . Current research is dedicated to pinpointing the ideal size that strikes a balance between efficient tumor accumulation and the ability to traverse compact tumor tissues. The shape of nanoparticles is another crucial factor influencing their interaction with biological systems. Rod-shaped or discoidal NPs have demonstrated superior cellular uptake and tissue penetration compared to spherical NPs 236 . This superior penetration is credited to their ability to navigate more readily between cells. Current research is investigating the effects of various NP shapes on biodistribution, cellular internalization, and therapeutic efficacy.

The surface charge of nanoparticles is a tunable feature that significantly influences their engagement with the TME 237 . Cationic NPs can more effectively interact with the negatively charged cell membranes, potentially boosting cellular uptake. However, this may also lead to increased clearance by the reticuloendothelial system 238 . Consequently, the formulation of methods to mask the positive charge under normal physiological conditions, while enabling charge exposure in the acidic TME, is a burgeoning field of research. Additionally, the decoration of NP surfaces with targeting ligands, such as antibodies, peptides, or small molecules, promotes the active targeting of specific cells within the TME. This targeted approach can enhance binding and uptake by the desired cell population, thus elevating the therapeutic index of the treatment 87 . Moreover, the integration of stimuli-responsive linkers that trigger the release of therapeutic agents in response to TME-specific stimuli, like pH fluctuations or enzymatic activity, is a promising strategy to enhance precision medicine 202 .

Application of nanotechnology in immune cell engineering

The convergence of nanotechnology and immune cell engineering is paving innovative avenues in the field of oncology 208 . Leveraging the unique properties of nanomaterials, scientists are developing strategies to enhance the precision targeting of tumors by immune cells, including T lymphocytes and NK cells 239 . A significant application in this domain is the use of nanotechnology for the genetic modification of immune cells. Techniques such as CRISPR/Cas9 can be combined with nanocarriers to precisely edit the genomes of T or NK cells, endowing them with improved abilities to detect and destroy cancerous cells 240 . These genetically modified immune cells, when equipped with nanomaterials, can serve as vectors for the targeted delivery of therapeutic agents to tumor sites 241 , 242 . Another technique was the development of the nanovaccines 243 . Recent research utilizes multi-lamellar RNA lipid particle aggregates that can significantly enhance the immunogenicity of tumor mRNA antigens, as demonstrated in both canine and human glioblastoma patients ( Fig. 5 ) 244 . Figure 5 Multi-lamellar RNA lipid particle aggregates enhance the payload packaging and immunogenicity of tumor mRNA antigens. (A) The illustration of the Mechanism of multi-lamellar RNA lipid particle in tumor microenvironment. (B) NanoSight size distributions. (C) C57Bl/6 mice bearing pulmonary B16F0 melanomas treated with anti-PD-L1 mAbs, with or without B16F0 tumor-derived RNA-LPAs. (D) Serum from canines was obtained for analysis of IFN- α , CCL2, monocyte count, lymphocyte count, and temperature in dogs. (E) Heatmaps displaying differential gene expression of antigen presentation in human. (F) Kaplan-Meier curve of receiving RNA-LPA compared with historical control of canines receiving supportive care. Reprinted with the permission from Ref. 203 . Copyright © 2024 CellPress. Figure 5

Moreover, nanotechnology is being utilized to fabricate advanced scaffolds and substrata that promote the proliferation and activation of immune cells 245 . These biomaterials can be designed to provide the necessary signals and environmental conditions that support the growth and maturation of immune cells, thereby increasing their effectiveness in targeting tumors. Additionally, nanoparticles are being investigated for the delivery of immunomodulatory agents. They can be engineered to encapsulate cytokines, immune checkpoint inhibitors, or other immunoenhancing substances, and deliver them with precision to the tumor immune microenvironment 246 . This targeted delivery may help to modulate the local immune response, overcoming the immunosuppressive barriers posed by the tumor and boosting the potency of the engineered immune cells.

Targeted drug delivery to metastatic sites

Navigating the complexities of metastatic tumor management in oncology is a formidable task, compounded by their varied characteristics and propensity for widespread dissemination. As we venture into the future of nanomedicine, a significant focus will be on developing targeted strategies that can preferentially direct therapeutic agents to these metastatic sites 243 . This will involve the use of sophisticated homing devices, which are designed to navigate the intricate and often elusive pathways that characterize metastatic spread. One innovative approach is the development of nanovaccines that specifically target lymph nodes, which are common sites for metastatic spread and crucial in the initiation of systemic immune responses 247 . These nanovaccines can be engineered to not only deliver therapeutic agents but also to activate the immune system in a targeted manner. By capitalizing on the lymphatic system's inherent cell and molecule trafficking, these nanovaccines can concentrate at metastatic locales, thereby amplifying the local therapeutic and immunostimulatory agent density.

The construction of nanovaccines is underpinned by the application of biomaterials and surface engineering strategies that facilitate the precise targeting of receptors or antigens present on metastatic cells or within the tumor immune microenvironment. Moreover, the integration of stimuli-responsive components paves the way for the conditional release of therapeutic agents, triggered by localized cues at the metastatic site, such as pH alterations or the presence of specific enzymatic activities 248 . Additionally, the convergence of nanotechnology with immune cell engineering promises a synergistic enhancement between cellular immunotherapy and nanoscale drug delivery. Immune cells, genetically modified and fortified with nanomaterials, can be navigated to metastatic sites where they can interact with indigenous immune cells, thereby aiding in the annihilation of tumor cells 111 , 208 . The forthcoming horizon of nanomedicine targeting metastatic sites is poised to embrace the incorporation of cutting-edge imaging technologies. These will serve to monitor the biodistribution and therapeutic efficacy of nanovaccines in real-time, enabling the dynamic recalibration of treatment approaches. Such adaptations will ensure the optimization of therapeutic agent delivery, thereby striving to achieve the most favorable outcomes for individuals confronting metastatic disease.

Overcoming drug resistance

Drug resistance is a formidable barrier to the effectiveness of cancer therapies, as tumor cells often develop ways to counteract the lethal effects of chemotherapeutic agents 249 . The advent of nanotechnology offers innovative tactics to tackle this issue, with nanoparticles being meticulously engineered to target and overcome drug resistance mechanisms. One such approach involves the simultaneous delivery of chemotherapeutic drugs along with substances that can dismantle resistance. These nanoparticles can be expertly designed to encapsulate both the therapeutic medication and molecules that counteract the molecular foundations of drug resistance 250 . These molecules could include inhibitors of efflux pumps, such as P-glycoprotein, which are often associated with resistance, or agents that disrupt the survival pathways activated in treatment-resistant cancer cells.

Moreover, the application of nanotechnology in molecular targeting has given rise to immunoliposomes 251 . These are specialized liposomes linked with antibodies that bind specifically to receptors overexpressed on cancer cells. The interaction between the antibody and the antileukocyte antibody promotes the internalization of the liposome, resulting in the intracellular release of the drug and potentially circumventing efflux pump mechanisms 252 . Additionally, the deployment of nanocarriers for the concurrent delivery of drugs and siRNA or gene therapies has become an influential method for regulating the expression of drug resistance genes 253 . By suppressing the expression of genes that drive drug expulsion or trigger survival pathways, this method can re-sensitize resistant cancer cells to chemotherapy ( Fig. 6 ). Figure 6 The future of nanoparticles in tumor microenvironment. Multifunctional nanoplatforms means integrating various therapeutic agents and imaging modalities onto a single particle, enabling a synergistic attack on cancer cells and real-time monitoring of treatment efficacy. Theranostics means advancing to a new level, where nanoparticles not only treat but also diagnose, providing a comprehensive tool for personalized medicine. Targeting metastasis means involving the development of nanoparticles capable of homing in on cancer cells that have spread to distant organs, such as the liver, lung, and intestine, thereby tackling one of the most aggressive aspects of cancer. Overcoming resistance means designing nanoparticles that can bypass or reverse the mechanisms that tumors use to evade therapeutic agents, ensuring sustained treatment effectiveness. Precision engineering means refining the size, shape, and surface properties of nanoparticles to maximize their interaction with target cells and minimize side effects on healthy tissues. Finally, immune cell engineering means harnessing the power of the immune system by designing nanoparticles that can activate and direct immune cells like T cells and macrophages to attack cancer cells more effectively. Figure 6

Nanoformulations from preclinical studies to clinical approval

The translation of nanomedicine from bench to bedside is fraught with intricacies and challenges. Ensuring the safe and effective transition of these therapies requires meticulous attention to several key issues. A primary challenge is the development of nanocarriers that are more targeted and less toxic. The design must enable specific targeting of disease sites while minimizing off-target effects and toxicity to healthy tissues, necessitating a profound understanding of the interactions between nanocarriers and biological systems, including immune responses and biodistribution 254 .

The elevated production costs also erect a significant barrier to clinical adoption. The creation and fabrication of nanocarriers frequently entail sophisticated procedures that necessitate state-of-the-art equipment and materials 255 . Achieving scalability while maintaining quality and affordability is a formidable challenge. Additionally, the establishment of quality control measures and standardized protocols further increases the cost and complexity of bringing these therapies to market 256 . Navigating the regulatory approval processes is another intricate hurdle for the clinical integration of nanomedicines. The regulatory frameworks for nanomedicines are in a state of evolution, necessitating clearer guidelines and standards for their safety, efficacy, and manufacturing 257 . The long-term effects of nanomaterials on the human body remain incompletely understood. There is a prevalent negative perception of nano-level waste, concerning both human health and the environment 258 , 259 . While nanomedicines hold significant therapeutic potential, concerns exist regarding their long-term safety profiles. The potential for accumulation, toxicity, and unforeseen interactions with biological systems must be thoroughly investigated through preclinical and clinical studies. A comprehensive grasp of the biodistribution and clearance mechanisms of nanocarriers is vital for safety assessment and for crafting nanomedicines with superior pharmacokinetics.

Beyond these challenges, additional factors complicate the clinical translation of nanomedicines. These include the need for more robust preclinical models that accurately replicate human diseases 260 , the development of sensitive and specific analytical techniques for tracking nanomedicines in vivo 261 , and a deeper comprehension of the mechanisms by which nanoparticles can enhance drug delivery and therapeutic outcomes 262 .

Conclusions

The integration of nanomedicine with cancer immunotherapy has shown remarkable progress, as demonstrated by the ability to effectively alter the TIM and enhance treatment outcomes. This article reviews the strategic application of nanotechnology to target and reshape the intricate cellular and molecular components of the TIM. Notably, the incorporation of nanomedicine in boosting immunotherapy has been illustrated through the use of liposomal doxorubicin (Doxil®), which has shown increased safety and tolerability in clinical applications, and has the potential to be combined with traditional chemotherapy and immune checkpoint inhibitors 169 , 263 , 264 . Furthermore, paclitaxel protein-bound particles, such as Abraxane®, have been formulated using innovative nanoplatforms, reducing solvent-related side effects and improving drug delivery and efficacy 265 , 266 , 267 . The emergence of theranostic nanoparticles marks a significant advancement in personalized medicine, allowing for the simultaneous performance of diagnostics and therapeutics. These nanoparticles, equipped with various imaging agents and therapeutic payloads, have been shown to increase the accuracy of cancer treatments and offer insights into the effectiveness of therapies 223 , 227 , 230 . Precision engineering of nanoparticles is also highlighted as a key strategy for optimizing cancer treatments. By adjusting the size, shape, and surface characteristics of nanoparticles, researchers have managed to improve their biodistribution, cellular uptake, and overall therapeutic efficacy 234 , 235 , 236 .

Despite the promise of nanomedicine in clinical translation, challenges remain, including the need for more targeted and less toxic nanocarriers, the high costs of production, and the dynamic regulatory environment 257 . It is also essential to ensure the safety and biocompatibility of nanomaterials, with ongoing studies focusing on their biodistribution, clearance, and long-term effects within the human body 268 , 269 , 270 . The future of nanomedicine in cancer therapy holds immense potential. The ongoing development of multifunctional nanoplatforms, the incorporation of theranostics into clinical practice, and the precision engineering of nanoparticles are expected to push the boundaries of personalized and effective cancer treatments. However, to realize this potential, it is necessary to overcome the current challenges and deepen the understanding of the intricate interactions between nanomedicines and biological systems.

Authors contributions

Nan Lin: Conceptualization, Writing – original draft. Keqin Tan: Conceptualization, Writing – original draft. Yuhao Wei: Data curation, Writing – original draft, Conceptualization. Songtao Xie: Writing – review & editing, Resources. Jiaming Liu: Writing – review & editing. Xuelei Ma: Writing – original draft, Conceptualization, Writing – review & editing.

Conflicts of interest

The authors have no conflicts of interest to declare.

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This article is part of a special issue entitled: Disease Microenvironment Modulation published in Acta Pharmaceutica Sinica B.

Peer review under the responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.