Liposomes consist of sterols, surfactants and natural or synthetic phospholipids, such as those that can be obtained from egg yolk, soybean and hydrogenated phosphatidylcholine, which are degradable, nontoxic and suitable for industrial production (32). In addition, liposomes are spherical vesicles with bilayer membranes (33). These bilayers are spontaneously formed by phospholipids dispersed in an aqueous phase medium, and the amphiphilic nature of liposomes makes them effective drug carriers (34) and significantly improves the transport of drugs across various lipid-based barriers (35). In addition, liposomes can improve the therapeutic efficacy of drugs by increasing drug solubility and reducing drug toxicity (36).

Liposomes have been used in a variety of therapeutic applications, such as anticancer drugs, antifungal drugs, antibiotics, gene therapy, anesthetic drugs, and anti-inflammatory drugs. Previous studies have revealed the ability of nanodrug delivery systems to modulate the tumor immune microenvironment and enhance the antitumor immune response (37, 38). Gu et al. (39)summarized the many advantages of liposomes as carriers, including their use as vaccines that stimulate immune responses, their ability to selectively deliver drugs to the tumor microenvironment, and their ability to be used in conjunction with other therapies, including chemotherapy, radiotherapy and photothermal therapy. Cheng et al. (40)mixed hydrogenated (soybean) L-α-phosphatidylcholine and 1,2-dioleoyl-3-trimethylammonium propane in a 100:1 weight ratio, dissolved them in chloroform and dried them with a rotary evaporator to form a lipid film. The liposomal nanoparticles were able to deliver cGAMP to macrophages via STING receptors in triple-negative breast cancer. cGAMP reprogrammed M2-like macrophages in the TME to M1-like macrophages and increased CD4⁺ and CD8⁺ T-cell infiltration, thereby enhancing the efficacy of breast cancer immunotherapy. In addition, many factors in the TME, such as temperature and pH, can influence the action of the TME; therefore, Fu et al. (41) developed a temperature-sensitive liposome-based delivery system, which was able to remodel the immune microenvironmental of tumor lymph nodes and induce immunogenic cell death in tumor cells after stimulation by photothermal therapy, thus increasing the levels of calmodulin and the secretion of high-mobility protein B1 to promote dendritic cell maturation. Fu et al. (41) also demonstrated strong antitumor immunotherapy against hot and cold tumors when used in combination with PD-L1 therapy. In addition to temperature-sensitive liposomes, pH-sensitive liposomes have been used for similar functions. CAFs are prevalent and engage with cancer cells and the adjacent tumor microenvironment (TME), significantly influencing tumor development, proliferation, and metastasis (42). Moreover, CAFs restructure the extracellular matrix by the secretion of growth factors, chemokines, and other tumor-enhancing substances (43). Consequently, there is a growing emphasis on CAFs and their integration with nanomaterials to modify the tumor microenvironment and improve the effectiveness of immunotherapy. Jia et al. (44) fabricated liposomes encapsulated in CAFs and tumor cell membranes that were able to specifically target CAFs and tumor cells. In addition to drug delivery, liposomal vaccines have shown great potential; a previous study revealed that a liposomal vaccine consisting of the cationic lipid DOTAP and loaded with mRNA was able to induce an immune response against melanoma (45).

Lipid nanoparticles (LNPs) are colloidal nanocarriers ranging from 1–100 nm in size. Compared with metal nanoparticles, LNPs are more easily removed and accumulate less in the human body; thus, LNPs are less toxic to organisms (46).

LNPs have been extensively studied for use in small interfering RNA (siRNA) and messenger RNA (mRNA) delivery. SiRNA largely addresses cancer by silencing genes, which is essential for tumor development. Among siRNA delivery techniques, liposomal nanoparticles are the most thoroughly investigated. Most siRNA nanoparticle delivery strategies depend on the increased permeability and retention (EPR) effect to increase tumor accumulation. The EPR effect can enhance the diffusion of siRNA nanoparticles to several organs (47).

Compared with cationic liposomes, these lipids are neutral at physiological pH, are protonated at low pH, and have the advantages of greater biocompatibility and lower cytotoxicity (48). CRISPR/Cas is a gene editing technology, the RNA and protein constituents of the CRISPR/Cas9 system are prone to degradation in the in vivo milieu. Lipid nanoparticles (LNPs) safeguard these components against degradation by nucleases and proteases via their lipid shell, thus extending their stability within the body. Altering the surface of lipid nanoparticles (LNPs) can diminish their identification by the immune system, hence reducing the immunogenicity of the CRISPR/Cas9 system in vivo. It has been shown that by embedding the CRISPR/Cas system into the LNP system, nanocarriers can be target and deliver the CRISPR/Cas system to cancerous tissues; moreover, by incorporating specific antibodies, nanocarriers can reduce off-target effects and enhance their targeting ability (49). Mennati et al. (50) prepared heterotrimeric LNPs loaded with siRNA and lycopene and demonstrated that blockade of the IGF-1R signaling pathway could inhibit cell proliferation and lead to programmed cell death and that LNPs significantly induced apoptosis and blocked the cell cycle in MCF-7 breast cancer cells. Zhang et al. (51) formulated an mRNA vaccine utilizing lipid analogs and designed and screened specific LNPs that activated Toll-like receptor 4 and induced T-cell activation; the results showed that the nanovaccine could deliver mRNAs to the DCs and promote antigen presentation; in addition, LNPs also have good immunogenicity and can induce T-cell activation, thus improving the immunotherapeutic effect on tumors ( Figure 5 ).

Dendritic macromolecules are nanoscale molecules with radial symmetry as well as well-defined, homogeneous, monodisperse structures. Dendritic polymers are usually between 4 and 20 nm in diameter, which is smaller than most nanoparticles and liposomes; this feature makes them potentially more advantageous in terms of interstitial diffusivity, cellular uptake volume and tissue penetration depth (52). Dendrimers are usually used as nucleic acid carriers, and in the treatment of cancer, nucleic acid therapy has a great advantage (53).

Zhan et al. (54) designed a nanomicelle composed of a phosphorus dendrimer and the chemotherapeutic drug doxorubicin, and the material combined with aPD-L1 treatment inhibited tumor growth, enhanced the apoptosis of B16 cells, induced immunogenic cell death, and promoted the proliferation and activation of natural killer cells, which in turn affected the TIME in a mouse melanoma model. Xiang et al. (55) developed an amphiphilic PAMAM G5 dendrimer that enhances the pH sensitivity of drugs in the TME. While Huang et al. (56) also developed the above dendrimer material and found that it was able to release Fe³⁺ and Cu²⁺ in a weakly acidic TME. Moreover, the targeted MR imaging of triple-negative breast cancer was achieved by modulating the TME with enhanced iron death and chemodynamic therapy. The TME contains a high concentration of glutathione (GSH), and glutathione enzymes can participate in the development of chemotherapeutic resistance, thus reducing the efficacy of conventional chemotherapeutic drugs (57). Zhang et al. (58) developed a smart nanomedicine formulation based on redox-responsive dendritic macromolecular nanogels, which not only has good biocompatibility and the ability to reduce the high concentration of GSH in the TME but also has the ability to activate tumor-infiltrating CD 4⁺ and CD 8⁺ T cells, in addition to being able to resist PD-L1 immune checkpoint blockade therapy, remodel the TIME and inhibit tumor growth.

Exosomes, also known as extracellular vesicles, are the smallest organelles, with a size of approximately 40–150 nm (59). Exosomes play important roles in human growth and development, immunomodulation, and tissue homeostasis (60), and they serve as versatile drug delivery vehicles that can be used to regulate immunity (61). In addition, although exosomes are similar to liposomes in shape and function, compared with liposomes, exosomes are retained in body fluids for a longer period of time and are not easily eliminated by macrophages or reticuloendothelial cells (62). In recent years, the application of exosomes in tumor immunity has become increasingly widespread; relevant studies have shown that miR-155 and miR-125b2 in exosomes can be used to reprogram tumor-associated macrophages, thereby inhibiting tumor progression (63). Fu et al. reported that exosomes derived from DCs can be loaded with a variety of peptide antigens and that they stimulate both CD4⁺ and CD8⁺ T cells, which participate in antitumor responses (64). M1-like macrophage-derived exosomes (M1-Exos) have inflammation-directed tumor-targeting ability, and relevant studies have shown their role in reprogramming the immunosuppressive TME (65). Zhen (66) developed an exosome bound to liposomes that could effectively alleviate hypoxia, increase ROS levels, promote the release of proinflammatory cytokines from M1-Exos and reprogram the immunosuppressive TME. Lv et al. (65) also developed a nanovesicle composed of exosomes and AS1411 aptamer-modified liposomes, which not only generate a large amount of reactive oxygen species to induce the apoptosis of tumor cells via near-infrared laser irradiation but also polarize TAMs and promote the infiltration of T lymphocytes, thus enhancing the antitumor immune response ( Figure 6 ).

Nanogels can be used as nanocarriers for systemic drug delivery. Nanogels take advantage of the combination of nanotechnology with gel-based materials such as hydrogels (67). Nanogels have unique physical and chemical properties, such as nanoscale size, tunable properties, significant hydration, good biocompatibility, etc. (68). Compared with conventional nanoparticles, they have variable particle sizes and shapes as well as greater sensitivity to external stimuli such as pH, temperature, ionic strength and redox conditions (69).

Bai’s team (70) developed a nanogel that responds to matrix metalloproteinase-2 in the TME and releases two types of liposomes at the tumor site; it not only promotes apoptosis but also triggers immunogenic cell death and promotes the maturation of DCs and T-cell infiltration, thus altering the immune-suppressive state of the TME and enhancing the therapeutic effect. In contrast, Li et al. (71) designed a biocompatible alginate-based hydrogel for codelivery of dextran nanoparticles encapsulated with pessidatinib and platelets modified with an anti-PD-1 antibody; this material was able to inhibit macrophage aggregation, significantly alleviate the immunosuppressive tumor microenvironment, promote infiltration of effector CD8⁺ T cells, and enhance the immunotherapeutic effect of tumors by depleting TAMs. In addition, Jiang et al. (72) developed an injectable hydrogel for the delivery of macrophage CAR gene-loaded nanocarriers and anti-CD47 antibodies capable of targeting glioma stem cells and triggering an antitumour immune response. Tian et al. (73) prepared a self-degradable nanogel that efficiently facilitated the infiltration and activation of CD8⁺ T cells and remodeled the immunosuppressive TME. Gao et al. (74) developed Vir-Gel, a membrane-encapsulated nucleic acid nanogel embedded with therapeutic miRNAs, which could induce the calibration of proinvasive M2 macrophages to antitumor M1 macrophages and enhance the immunotherapeutic efficacy in glioma.

Polymeric nanoparticles (PNPs) are entities whose size falls within the range of 1 to 1000 nm, mainly including nanospheres, nanocapsules, and polymeric micelles (75). Polymeric nanoparticles are usually characterized by good biocompatibility, modifiability, etc., and can be either derived from nature or artificially synthesized. Chitosan, as a type of polymer nanoparticle, is derived mainly from the deacetylated form of chitin; it is one of the best drug carriers for the treatment of cancer (76). Micelles are nanocolloidal particles formed by the assembly of amphiphilic polymers. Targeting CAFs is one strategy in tumor immunotherapy, and Cheng et al. (77) demonstrated that polymeric micelles can noncovalently bind CAF-targeted antibody fragments, thus improving the efficacy of immunotherapy. Wang et al. (78) integrated paclitaxel, thioridazine and the small-molecule PD-1/PD-L1 inhibitor HY19991 into a dual-enzymatic pH-sensitive polymer structure that was able to release paclitaxel in the acidic TME. This approach was almost always able to alleviate the immunosuppressive TME in a mouse model of MCF-7 metastatic breast cancer (79). In addition, Wan (80) synthesized a micellar system assembled with gemcitabine-conjugated polymer (PGEM), a CCR2 antagonist PF-6309, for cancer therapy; PGEM was shown to activate the STING signaling pathway in DCs, which enhanced natural killer cell and adaptive antitumor T-cell responses and reduced the aggregation of TAMs. Groettrup et al. (81) created a new type of cancer nanovaccine using PLGA and riboxxim. This vaccine can activate the immune response by triggering endosomal Toll-like receptor 3. Dacoba et al. (82) designed nanocomplexes capable of targeting and delivering the Toll-like receptor 3 agonist poly(I:C), and in vitro experiments revealed that poly(I:C) delivered by this nanocarrier was more efficiently internalized by macrophages, which facilitated macrophage polarization toward the M1 phenotype, thereby enhancing their antitumor effects.

Guo et al. (83) prepared organic complex nanoparticles with photothermal capability, which, while being controllable for photothermal therapy and reducing damage to the surrounding tissues, were also able to significantly increase the infiltration of CD4⁺ and CD8⁺ T cells in the TME, downregulate the expression of PD-L1, and increase the proliferation and activity of cytotoxic T lymphocytes, thus improving the antitumor immune response of the organism (See Table 2 ) ( Figure 7 ).

Metal ions are vital to tumor immunomodulation, and some scholars have proposed the use of cancer metal immunotherapy (87). Combining metal ions with nanomaterials and preparing corresponding metal nanoparticles can modulate the immune response to tumors. Metallic nanoparticles can be designed to enhance biocompatibility and reduce toxicity to normal tissues by modifying their surface. In addition, metallic nanoparticles can act on tumor cells, immune cells and the extracellular matrix simultaneously to modulate the TME and enhance therapeutic effects.

Among many metal nanoparticles, gold nanoparticles are widely used because of their good biocompatibility and stability (88). Gold nanoparticles can induce an effective immune response at low doses (89). Liang et al. (90) subcutaneously injected gold nanomaterials encapsulated in liposomes into tumor-bearing mice, and 12 hours after the injection, the composite nanoparticles reached maximum accumulation in local lymph nodes and significantly promoted the maturation of dendritic cells, indicating that gold nanomaterials can be used to activate immune cells and enhance immune responses.

In contrast, among inorganic nanomaterials, only iron-based nanoparticles are approved by the FDA for medical use (91). Iron-based nanomaterials can enhance the killing effect on tumor cells through the Fenton reaction (92). Zhang et al. (93) developed nanomaterials consisting of Fe/Cu-based metal–organic frameworks, lactic acid oxidase and hyaluronic acid, which were able to increase the level of intracellular reactive oxygen species (ROS) via the glycolysis, which then promoted the repolarization of TAMs and enhanced the efficacy of immunotherapy.

CAFs inhibit the activity of immune cells by secreting immunomodulatory factors, which in turn promote the accumulation of immunosuppressive cells, such as Tregs and MDSCs, thereby helping tumor cells evade immune surveillance (94). Therefore, Bromma et al. (95) assayed gold nanoparticles modified with polyethylene glycol and arginine-glycine-aspartic acid peptides on the surface inside tumor cells and reported that the nanoparticles were able to increase cellular uptake and significantly reduce the tumor volume. In photodynamic therapy (PDT), photosensitizers are used to generate reactive oxygen species (ROS) under specific light irradiation, which is able to induce tumor cell death and amplify the efficacy of tumor immunotherapy (96). Zhou et al. (97) prepared ferritin nanoparticles, which are able to deliver photosensitizers to CAFs, significantly increase their photosensitizer accumulation at the tumor site, and also generate an immune response toward CAFs, thus enhancing the effect of immunotherapy. Ding et al. (98) formulated a vaccine (ZPM@OVA-CpG) that was able to release Zn²⁺ in a controlled manner and improve immunotherapy efficacy. Deng et al. (99) demonstrated the ability of a calcium-manganese bionic hybrid nanostimulant to activate both apoptosis and the innate immune response in ferrocytes, which provided a new therapeutic idea for the effective immunotherapy of triple-negative breast cancer. Cen et al. developed a functional immunotherapy for triple-negative breast cancer.

Metal oxide nanomaterials are nanoscale materials composed of metal and oxygen, mainly zinc oxide, iron oxide and other nanomaterials. Sun et al (100). prepared a hyaluronic acid-optimized magnetic nanoparticles (Fe₃O₄), which can not only efficiently penetrate into the interior of tumors but also adhere to CD44 receptors on the surface of tumor cells via hyaluronic acid to achieve specific targeting of tumor cells. In addition, these nanoparticles can regulate TAM repolarization and stimulate tumor cells and macrophages to secrete more chemokines. In contrast, Yang’s team (101) engineered a novel biomimetic magnetic nanoparticle, Fe₃O₄-SAS@PLT, which not only elicits tumor-specific immune responses but also effectively repolarizes macrophages from the immunosuppressive M2 phenotype to the antitumor M1 phenotype, in addition to depleting glutathione (GSH).

ROS can modulate the TIME and promote the infiltration and activation of immune cells, thereby enhancing antitumor responses. ROS usually act as intermediate signaling molecules, affecting the differentiation, function, and secretion of TAMs (102). Previous studies have shown that ROS-scavenging nanozymes can inhibit the transformation of macrophages into M2 TAMs by suppressing the activity of the ERK and STAT3 signaling pathways (103). Therefore, Gong et al (104). used bimetallic oxide FeWOX nanosheets in combination with a CTLA-4 checkpoint blocker and reported that ROS-mediated inflammation induced by FeWOX nanosheets in the TME can activate the immune system and trigger a strong immune response, which not only promotes the maturation of DCs, increases the number of T cells, and decreases the number of Tregs but also induces the repolarization of TAMs, thus effectively inhibiting tumor growth. Wu et al. (105) prepared a composite metal oxide nanomaterial of titanium carbide-chitosan-manganese iron oxide (MnFe₂O₄) that was able to catalyze the oxidation of glutathione to oxidized glutathione, thus depleting excess glutathione in the TME and increasing ROS generation and therapeutic effects ( Figure 8 ).

Non-metallic nanoparticles are particles at the nanoscale composed of non-metallic elements or non-metallic compounds. Graphene oxide nanosheets prepared by Guo et al. (106) were not only able to stimulate the polarization of M1-type macrophages but also were able to increase the levels of proinflammatory cytokines and chemokines, such as IL-12 and TNF-α, in the TME, thereby enhancing the antitumor immune response. A graphene quantum dot capable of forming a heterogeneous structure by combining with copper-based nanomaterials was prepared by Yan et al. and was able to promote the activation of immune cells directly or indirectly through its own properties, in addition to targeting and damaging DNA, thereby releasing tumor-associated antigens and promoting the maturation of DCs and the activation of T cells. In addition, selenium nanoparticles prepared by Xiong et al. (107) were able to promote ROS generation in tumor cells, leading to elevated levels of oxidative stress and thereby inhibiting tumor cell growth and proliferation. Xu et al. (108) synthesized PAP-SeNPs by integrating selenium nanoparticles with polysaccharides derived from Pholiota adiposa. Utilizing the diverse benefits of polysaccharides, including their degradability and biocompatibility, they improved the stability of selenium nanoparticles. These nanoparticles effectively targeted M2 TAMs and induced their polarization into the M1 phenotype, which exhibits anticancer properties. Li et al. (109) created a nanoplatform (Nano-Bi₂Se₃@MnCaP). This platform’s photodynamic treatment (PDT) can efficiently induce immunogenic cell death, stimulate the immune system, facilitate dendritic cell maturation, and activate T cells, therefore augmenting the antitumor immune response.

Mesoporous silica nanoparticles have excellent drug-carrying capacity and good hydrophilicity and have great potential for development (110). Zhao et al. (111) loaded acidic, environment-responsive CCM-encapsulated mesoporous silica nanoparticles with dacarbazine and combined them with aPD1. These nanoparticles not only induced an antitumor immune response in T cells but also effectively inhibited the growth and metastasis of melanoma. Wang et al. (112) prepared hollow mesoporous silica (HMS) nanospheres, which were able to promote the maturation of DCs. In addition, the HMS cancer vaccine exerted a synergistic effect with anti-PD-L1 antibodies on the tumor, which effectively increased the levels of CD4⁺ and CD8⁺ T cells and ultimately inhibited the growth of tumors (see Table 3 ) ( Figure 9 ).