The extracellular matrix (ECM) is a physical barrier that severely hinders the deep penetration of photothermal agents and immune cells, which is a major challenge to the efficacy of tumor photothermal immunotherapy. In this study, a visible tumor-targeting platelet membrane-wrapped biohybrid vehicle was developed to potentiate photothermalimmunotherapy through cancer-associated fibroblasts (CAFs) reprogramming. This system integrated IR820-modified platelet membrane and manganese-polyphenol nanoparticlesloaded with losartan. Based on the image contrast signals from IR820 and manganese ions, the biohybrid system enabled visual delivery under the guidance of fluorescence-magnetic dual-modal imaging. After reprogramming CAFs to a quiescent state with released losartan, the ECM was remodeled. The attenuated physical barrier and platelet carriers collectively facilitated the deep penetration of photothermal agents, improving the sensitivity of photothermal therapy. Moreover, the synergistic strategy of photothermal stimulation and CAFs regulation simultaneously activated the systemic immunity and alleviated the immunosuppressive tumor microenvironment. The biohybrid delivery system effectively reconstructed the anti-tumor immune defense system to boost the efficacy of photothermal immunotherapy through a positive feedback mechanism. STATEMENT OF SIGNIFICANCE: The dense extracellular matrix (ECM) constitutes a major physical barrier that severely restricts the penetration of photothermal agents and immune cells into tumors, thereby substantially limiting the efficacy of photothermal immunotherapy. A key cause of this barrier is cancer-associated fibroblasts (CAFs), which also suppress immunity. Reverting CAFs to a quiescent state or reprogramming them toward a tumor-suppressive phenotype offers a promising strategy to ameliorate ECM deposition and reverse immunosuppression. A visible tumor-targeting platelet membrane-wrapped biohybrid vehicle was developed to potentiate photothermal-immunotherapy through CAFs reprogramming. This intervention disrupts the stromal barrier and mitigates immune suppression for boosting anti-tumor immunity. Furthermore, the system enables real-time, dual-modal MRI-fluorescence imaging, providing a visual guidance platform for precision photothermal immunotherapy.

Cuproptosis represents a promising avenue for cancer immunotherapy, yet its efficacy is limited by difficulties in achieving targeted mitochondrial copper ion accumulation and upregulating cells reliance on mitochondrial respiration. To address this, we develop a biomimetic copper-based nanoplatform (SCTDM) coated with macrophage-tumor cell hybrid membranes (HM) and co-loaded with the lactate modulator syrosingopine (Su3118) and the copper ionophore disulfiram (DSF). SCTDM integrates active tumor targeting, in situ photothermal therapy (PTT), and lactate metabolism modulation, synergistically enhancing cuproptosis and antitumor immunity. SCTDM releases copper ions and DSF to facilitate mitochondrial copper ions delivery and induce immunogenic cell death (ICD). In the high hydrogen sulfide (H2S) tumor microenvironment (TME), copper ions further form photothermal copper sulfide complexes that enhance PTT efficacy and reactive oxygen species (ROS) generation, thereby augmenting cuproptosis. Notably, the liberated Su3118 selectively inhibits monocarboxylate transporters (MCT1/4), suppressing lactate efflux while simultaneously sensitizing cells to cuproptosis by disrupting glycolysis and restoring mitochondrial respiration. Collectively, the synergistic combination of PTT and lactate metabolism modulation serves to potentiate cuproptosis-induced immunogenic cell death. This cascade effect culminates in the reprogramming of the immunosuppressive TME and augments anti-tumor immunity for eradicating primary tumors and preventing recurrence.

The pathogenesis of inflammatory bowel disease (IBD) involves a self-perpetuating cycle driven by oxidative stress, microbial dysbiosis, and immune dysregulation. Restoring intestinal microbiota homeostasis and immune balance is therefore critical for intestinal health and long-term disease remission. In this study, an M2 macrophage-based biohybrid system (GaInMg@PDA@M2) was constructed to achieve synergistic intervention against these multiple pathological pathways. This biohybrid system utilized M2 macrophages with inherent inflammatory tropism as delivery vehicles, loaded with multifunctional nanoparticles (GaInMg@PDA) composed of liquid metal (GaIn), magnesium ions (Mg²⁺) and polydopamine (PDA). The nanoparticles effectively scavenged reactive oxygen species and exhibited synergistic antibacterial effects with the GaIn component, while the released Mg²⁺ further promoted macrophage polarization towards the anti-inflammatory M2 phenotype. In a DSS-induced murine colitis model, GaInMg@PDA@M2 demonstrated inflammatory targeting for the diseased colonic tissue and significantly ameliorating clinical symptoms including disease activity index, colon shortening and histopathological damage. The therapeutic mechanisms involved downregulation of pro-inflammatory cytokines, upregulation of anti-inflammatory cytokines, enhancement of antioxidant enzyme activity, restoration of intestinal tight-junction protein expression, and rebalancing of gut microbiota homeostasis. This "cell-homing and multi-effect synergy" strategy represented a precise therapeutic approach capable of disrupting the key pathological cycle in IBD. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD) is driven by a self-perpetuating cycle of oxidative stress, microbial dysbiosis, and immune dysregulation, making restoration of intestinal ecosystem balance a major therapeutic challenge. Conventional therapies often lack specificity or fail to address these interconnected pathologies simultaneously, owing to systemic side effects, non-specific immunosuppression, and diminished efficacy over time. In response, a paradigm shift toward a multi-targeted strategy that concurrently tackles oxidative stress, corrects dysbiosis, and resolves inflammation is imperative to break this cycle. To this end, an M2 macrophage-based biohybrid system was developed to achieve synergistic intervention across these key pathological pathways, overcoming the limitations of conventional drugs and enabling simultaneous modulation of multiple core disease mechanisms.

The intratumoral microbiome has emerged as a critical component of the tumor microenvironment (TME), playing a significant role in tumorigenesis, pathological classification, metastasis, and prognosis. The nutrient-rich, hypoxic, acidic, and immunosuppressive nature of the TME facilitates the establishment of diverse intratumoral microbiome communities. In turn, the intratumoral microbiome further contributes to the formation of cold TME through mechanisms such as genetic and epigenetic alterations, pro-inflammatory responses, immune modulation, tumor metastasis, and enhanced drug resistance. Targeting and eliminating the intratumoral microbiome using nanotechnology presents a unique therapeutic strategy for overcoming chemotherapy resistance and improving the immunosuppressive TME. This review summarizes the microbial characteristics of various tumors and microbiome-mediated oncogenic mechanisms, with particular emphasis on recent advancements in nanotechnology aimed at eliminating the intratumoral microbiome and reprogramming the cold TME, thereby enhancing the efficacy of tumor immunotherapy. Our aim is to provide valuable insights to strengthen the effectiveness of tumor immunotherapy.

The key to achieving synergistic ferroptosis immunotherapy is enhancing the iron content in tumor cells, improving specific immunity, and regulating the tumor microenvironment. In this study, a drug-free biohybrid system targeting ferritin is developed using M1 macrophage microvesicles and HKN15-modified Prussian blue nanoparticles for synergistic ferroptosis immunotherapy. HKN15-modified nanoparticles simultaneously enhance iron content by activating endogenous iron ions and replenishing exogenous iron ions, which disrupts iron homeostasis for inducing ferroptosis in tumor cells. Photothermally enhanced ferroptosis based on Prussian blue nanoparticles also stimulates dendritic cell maturation. Moreover, M1 vesicles and iron ions from Prussian blue nanoparticles promote macrophage polarization to improve specific immunity. The mutual promotion of ferroptosis and antitumor immunity effectively results in a synergistic therapeutic circuit for inhibiting tumor growth and preventing cancer recurrence and metastasis in 4T1 tumor-bearing female mice, thus offering a promising strategy for drug-free biohybrid system-mediated ferroptosis immunotherapy.

Photothermal therapy (PTT) or cuproptosis based on copper ions is a crucial strategy for precise colon cancer treatment. The excessive demand for tumoral accumulation of copper ions is essential to realize cuproptosis and in situ PTT simultaneously. Herein, a biomimetic nanoplatform ZCESM@mem was fabricated to achieve an efficient copper ions transport for the combination of cuproptosis and in situ photothermal therapy. ZCESM@mem specifically targeted to tumors via the tumor biotaxis of macrophage membranes coating, and subsequently achieved endogenous H2S-triggered in situ PTT with the generation of photothermal agent copper sulfide in special colon cancer microenvironment, resulting in direct hyperthermia ablation. Moreover, the degraded nanoplatform in acidic microenvironment released the copper ionophores elesclomol to accelerate the transport and accumulation of copper ions at mitochondria for inducing the PTT-promoted cuproptosis. The combined cuproptosis and PTT induced immunogenic cell death, activated the robust immune response and reprogrammed the immunosuppressive tumor microenvironment, demonstrating potent efficacy in inhibiting tumor proliferation and recurrence. Collectively, this study developed an efficient copper ion transport nanoplatform with integrated functions as cuproptosis and in situ endogenous H2S-triggered PTT for boosting colon cancer immunotherapy.

Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel "two birds with one stone" technique for amplifying enzyme-mediated tumor apoptosis and enzyme-promoted metabolic clearance is proposed and achieved using GOx-functionalized rhenium nanoclusters-doped polypyrrole (Re@ReP-G). Re@ReP-G reduces ATP production while increasing H2O2 concentrations in the tumor microenvironment through GOx-induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti-apoptotic Bcl-2 proteins, the upregulation of pro-apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser-induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, H2O2 catalyzes the conversion of rhenium nanoclusters in Re@ReP-G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP-G-based "two birds with one stone" therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms.

A cancer vaccine based on nano-adjuvant fusion represents an effective strategy for anti-tumor immunity. Compared with other cancer vaccine formulations, the ones based on apoptotic bodies not only possess higher load-bearing capacity and biosafety, but also present greater clinical translational potential. In this study, we developed an optically responsive cancer vaccine that induced robust anti-tumor immunity by encapsulating genipin-crosslinked nano-adjuvants in tumor cell apoptotic bodies. The vaccine may potentially be used for prophylactic or therapeutic purposes. As an antigen source and a cargo vehicle, apoptotic bodies can co-deliver antigens and adjuvants simultaneously to antigen-presenting cells to activate T cells. Nano-adjuvants promote the targeted delivery of adjuvants for effective immune responses. Genipin-crosslinked nano-adjuvants enable visual tracking of the tumor vaccine. In addition, the photothermal properties of genipin-crosslinked nano-adjuvants promote lysosomal escape of tumor antigens to enhance cross-presentation. These characteristics enable visualization and controllability of cancer vaccines, thereby avoiding the need for exogenous photosensitive reagents. Apoptotic body-based vaccines can be used to prevent or treat tumors by triggering a strong systemic immune response by promoting T-cell infiltration and improving the tumor immune microenvironment.

The theory of “seed and soil” illustrated that the tumor microenvironment and circulating tumor cells (CTCs) facilitated the tumor relapse and metastasis. An effective strategy should synergetically eliminate the seeds cells and reshape the tumor microenvironment. Herein, a platelet-hitchhiking biomimetic nanoplatform was constructed to pry precisely tumor seed and growing soil for inhibiting tumor recurrence and metastasis via “platelet bridge”. Benefiting from the PSN peptides, the nanoplatform captured and eliminated CTCs accurately in blood by specifically binding between PSN peptide and surface P-selectin on activated platelets, thus inhibiting hematogenous metastasis. Attributing to precise delivery from tumor targeting of the cell membrane and fluorescence imaging guidance of new indocyanine green, the nanoplatform accumulated at primary tumor. Triggered by the external laser and acidic tumor microenvironment, it degraded and robustly released doxorubicin and zinc ions. Along with the onsite photothermal combined chemotherapy, the excessive zinc ions disturbed the energy metabolism for triggering immune response. They together regulated immune suppressive microenvironment to prevent tumor invasion and metastasis. The platelet-hitchhiking biomimetic nanoplatform interfered the “seed and soil” crosstalk to achieve a two-pronged approach of eliminating the CTCs and reshaping tumor microenvironment, which synergistically inhibited multiple pathways in the tumor recurrent and metastasis cascade.

Tumor-associated macrophages (TAMs) are pivotal within the immunosuppressive tumor microenvironment (TME), and recently, have attracted intensive attention for cancer treatment. However, concurrently to promote TAMs repolarization and phagocytosis of cancer cells remains challenging. Here, a TAMs-targeted albumin nanoparticles-based delivery system (M@SINPs) was constructed for the co-delivery of photosensitizer IR820 and SHP2 inhibitor SHP099 to potentiate macrophage-mediated cancer immunotherapy. M@SINPs under laser irradiation can generate the intracellular reactive oxygen species (ROS) and facilitate M2-TAMs to an M1 phenotype. Meanwhile, inhibition of SHP2 could block the CD47-SIRPa pathway to restore M1 macrophage phagocytic activity. M@SINPs-mediated TAMs remodeling resulted in the immunostimulatory TME by repolarizing TAMs to an M1 phenotype, restoring its phagocytic function and facilitating intratumoral CTLs infiltration, which significantly inhibited tumor growth. Furthermore, M@SINPs in combination with anti-PD−1 antibody could also improve the treatment outcomes of PD−1 blockade and exert the synergistic anticancer effects. Thus, the macrophage repolarization/phagocytosis restoration combination through M@SINPs holds promise as a strategy to concurrently remodel TAMs in TME for improving the antitumor efficiency of immune checkpoint block and conventional therapy.

During wound healing after cancer surgery, platelets, neutrophils, and macrophages accumulate at the wound site and induce important pathophysiological features. Utilizing these pathophysiological features, the development of targeted delivery systems for postoperative tumor immunotherapy is an important strategy. Herein, a twindrive precise delivery system of hybrid membrane combined with CD47 blocking is developed for targeted delivery and targeted regulation to induce postoperative immunotherapy. The precise delivery system consists of IR820-modified platelet-neutrophil hybrid membranes loaded with R848 nanoparticles. Based on the pathological characteristics of platelet aggregation and neutrophil tendency caused by the wound inflammatory microenvironment after tumor surgery, the twindrive delivery system could achieve targeted delivery and targeted regulation of immune drugs to tumor sites. After precise delivery guided by fluorescence imaging, R848 is targeted to reprogram M2 macrophages into M1 macrophages, stimulate dendritic cell maturation as an adjuvant, and then activate T cell immunity. R848 polarization and CD47 blockade together enhanced the phagocytosis function of macrophages, which combined with T cell-mediated cellular immune response to finally effectively inhibit postsurgical tumor recurrence, metastasis, and prolonged survival time. It develops a targeted delivery and regulatory system for cell-specific responses to the pathophysiological features of wound healing for postoperative immunotherapy.

The regulation of tumor immunosuppressive microenvironments via precise drug delivery is a promising strategy for preventing tumor recurrence and metastasis. Inspired by the stealth strategy, a stealthy nanovehicle based on neutrophil camouflage is developed to achieve precise delivery and tumor immunotherapy by triggering pyroptosis. The nanovehicle comprises anti-CD11b- and IR820-conjugated bovine serum albumin nanoparticles loaded with decitabine. Camouflaged by neutrophils, the nanovehicles achieve efficient tumor delivery by neutrophil hitchhiking owing to the biotropism of neutrophils for tumors. The fluorescent signal molecule, IR820, on the nanovehicle acts as a navigation monitor to track the precise delivery of the nanovehicle. The released decitabine upregulates gasdermin E, and laser irradiation activates caspase-3, thereby resulting in pyroptosis, which improves the system's adaptive immune response. In a triple-negative breast cancer animal model, it regulates the immunosuppressive microenvironment for effective tumor immunotherapy and induces a long-lasting and strong immune memory to prevent lung metastasis.

Tumor precision therapy and preventing tumor recurrence and metastasis are the main challenges to tumor eradication. Herein, an apoptotic body-based vehicle with imaging navigation is developed for precise tumor delivery and photothermal-immunotherapy by IR820-conjugated apoptotic body loaded with R848 nanoparticles. The apoptotic body serves as ammunition stores as well as vehicle drive engines, while IR820 acts as a fluorescence imaging navigation and photothermal controlling system. The apoptotic body vehicle can deliver the ammunition to tumor and achieve deep penetration by macrophage-hitchhiking. Fluorescence imaging navigation opens a control window for photothermal treatment, followed by photothermal triggering of in situ vaccine formation. Further, CD47 antibody loaded hydrogel strengthens innate and adaptive immunity, simultaneously the polarization of macrophages regulates the immunosuppressive microenvironment to further promote the combined antitumor immunotherapy. With breast tumor (4T1)-bearing mice model, the apoptotic body vehicle performs excellent therapeutic efficacy for primary tumor, distant tumor, tumor metastasis, and recurrence prevention.

Pyroptosis-based immunotherapy can escape drug resistance as well as inhibit metastasis. It is urgently required to develop a delivery platform to induce targeted tumor-specific pyroptosis for cancer immunotherapy. Herein, macrophages-based biohybrid microrobots (IDN@MC) are constructed with IR-macrophage and decitabine-loaded Metal-organic frameworks (DZNPs). The integration of fluorescence photosensitizers and pH-sensitive DZNPs endow the microrobots properties such as photothermal conversion, fluorescent navigation, targeted drug delivery, and controlled drug release. In light of the inherent tumor targeting, tumor accumulation of IDN@MC is facilitated. Due to the sustained release of decitabine from packaged DZNPs, the host macrophages are differentiated into M1 phenotypes to exert the tumor phagocytosis at the tumor site, directly transporting the therapeutic agents into cancer cells. With laser control, the rapid and durable caspase 3-cleaved gasdermin E (GSDME)-related tumor pyroptosis is achieved with combined photothermal-chemotherapy, releasing inflammatory factors such as lactate dehydrogenase and interleukin-18. Subsequently, the robust and adaptive immune response is primed with dendritic cell maturation to initiate T-cell clone expansion and modulation of the immune suppressive microenvironment, thus enhancing the tumor immunotherapy to inhibit tumor proliferation and metastasis. This macrophages-based biohybrid microrobot is an efficient strategy for breast cancer treatment to trigger photo-induced pyroptosis and augment the immune response.

Controllable and visible delivery of therapeutic agents is critical for tumor precise therapy. Tumor targeting and deep penetration of therapeutic agents are still challenging issues for controllable delivery. Visible drug delivery with imaging navigation can optimize the treatment window for personalized medicine. Herein, a biomimetic platelet intelligent vehicle with navigation (IRDNP-PLT) was developed to achieve controllable and visible delivery with a navigation system, a driving system, and a loading system. The platelets acted as engines and drug repositories to exert the target driving and delivery functions. The fluorescent photothermal agent IR-820 was introduced in the platform to offer an imaging navigation for the intelligent platelet vehicle in addition to photothermal therapy. The nanodrug-loaded platelets enabled efficient drug loading and controlled release of the therapeutic payload by encapsulating photothermal-/pH-sensitive chemotherapeutic nanoparticles (PDA@Dox NPs). In in vivo experiments on 4T1 tumor-bearing mice models, IRDNP-PLT performed well in tumor targeting and showed excellent therapeutic efficacy and tumor recurrence prevention ability. The intelligent platelet vehicle achieved the functions of tumor targeting and deep penetration, fluorescence imaging guidance, photocontrolled drug release, and chemo-photothermal combination therapy, suggesting the advancement for tumor precise delivery and efficient therapy.

Precise delivery and responsive activation of therapeutic agents are critical for tumor precise therapy. Herein, inspired by intelligent express, a nanozyme-laden intelligent macrophage express was fabricated based on IR 820-macrophage loaded with GOx nanozymes for tumor-targeted photothermal-amplified starvation therapy with fluorescence imaging guidance. The nanozyme-laden intelligent macrophage express exerted precise delivery through cargo loading, conveying and unloading. For efficient cargo loading, H2O2-sensitive GOx nanozymes with blocked enzymatic activity were packaged on macrophage expresses with excellent phagocytic ability. Due to the inherent tumor tropism, the therapeutic agents-laden macrophage expresses naturally accumulated at tumor site with fluorescence navigation to track the conveying process. The spatiotemporal unpacking of the laden therapeutic agents at tumor site was triggered by the external laser for the macrophage express photothermal property. The released special tumor-microenvironment responsive GOx nanozymes were activated by H2O2 in tumor to start starvation therapy. Photothermal therapy generated mild hyperthermia and starvation therapy produced H2O2 further increased the nanozymes enzymatic activity, enhancing GOx-mediated starvation therapy. The nanozyme-laden intelligent macrophage express integrated laser-induce drug release and activation, tumor microenvironment-responsiveness, and circular amplification property, achieving the synergistic effects of PTT and starvation therapy in vitro and in vivo.

Accurate and efficient antigen delivery is crucial for inducing a strong and long-term immune response. A visible protein nanovaccine made from antigen could provide a novel and promising technology for secure and efficient delivery of the antigen with imaging visualization. In this study, a functional nanovaccine based on genipin crosslinked ovalbumin (OVA) fluorescent nanoparticles with chitosan (CS-OVA-NPs) was developed. The nanovaccine can carry abundant antigens by self-crosslinking without additional carriers. The fluorescence imaging technique was applied to monitor and reveal the process of antigen delivery in vivo based on the fluorescence of genipin with a non-invasive and real-time manner. This functional OVA nanovaccine can enhance the uptake of OVA in Dendritic Cells (DCs) and further promote DCs to maturate in vitro. In vivo study further indicated CS-OVA-NPs could trigger antigen-specific immune responses, which demonstrated that this fluorescent nanovaccine provided a novel design approach for accurate and efficient vaccine delivery.

Natural killer (NK) cells exert cytotoxic effects against infected or stressed cells, such as tumor cells, without the limitation of major histocompatibility complex (MHC) I. NK cells secrete perforins to form tunnels to mediate the entry of granzyme into target cells. This strategy, selected by natural evolution, provides a feasible method for the delivery of antitumor drugs against intracellular targets, and avoids drug-resistant mechanisms in tumor cells, such as the pumping out of drugs mediated by multidrug resistance. We constructed pH-labile artificial NK cells (ANKC) based on nature to mediate high levels of drugs in tumor cells to overcome tumor drug resistance. Mesoporous silicon nanoparticles (MSNs) modified with benzaldehyde were designed to function as scaffolds for ANKC. Doxorubicin (Dox), a model antitumor drug, was loaded into the pores of MSNs. Melittin, a pore-forming peptide, was utilized as the gate for mesopores with an acid-labile Schiff base linkage. pH-labile ANKC released melittin and Dox in slightly acidic tumor microenvironments. Melittin, like perforin, assembled tunnels on the plasma membrane or endosome, ensuring the intracellular transportation of Dox. Dox, similar to granzyme, induced the apoptosis of tumor cells. The combinational treatment partially eased the drug resistance mechanism, such as pumping out of drugs, by continuous intracellular drug accumulation mediated by melittin pores. The pH-labile ANKC demonstrated significant Dox enrichment in drug-resistant MCF-7/Adr cells and MCF-7/Adr-based xenograft tumors in a mouse model, which eventually contributed to efficient inhibition of the proliferation and growth of MCF-7/Adr tumors. PH-labile ANKC provided a potential strategy to treat drug-resistant tumors.

Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis therapy and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. Herein, a hydrogel/nanosystem-mediated antiangiogenesis combined immunotherapy strategy was used to regulate the tumor microenvironment by the controlled release of apatinib, CD47 antibody (aCD47), and CpG. The combination of hydrogel with nanoparticles protected drug activity and maintained a long-term slow release of the drug for maximum synergistic efficacy. Apatinib promotes vascular normalization in tumors and enhances the efficacy of aCD47-based immunotherapy. The addition of Immunoadjuvant CpG further enhanced antigen presentation and stimulated the anti-tumor activity of macrophages to strengthen the efficacy of antiangiogenesis combined immunotherapy. The main effector immune cells, including CD4+ T, CD8+ T, NK, and activity DCs, were significantly increased after combination treatment, while the proportion of various immunosuppressive cells decreased significantly, especially MDSCs and M2-polarized macrophages. Based on an effective systemic immune response, the hydrogel/nanoparticle-mediated cooperative combination of antiangiogenesis and immunotherapy enhanced the synergistic effect for primary tumors and prevented metastasis for tumor treatment. The biomaterial-mediated antiangiogenesis combined immunotherapy strategy is a promising strategy for effective immunotherapy. STATEMENT OF SIGNIFICANCE: Relieving immunosuppression of the tumor microenvironment is the key to restoring and rebuilding the normal anti-tumor immune defense of the body. Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. For the combination of antiangiogenesis and immunotherapy, effective drug delivery to overcome local immune tolerance and regulate the tumor microenvironment to increase therapeutic effects is an important issue. The hydrogel/nanomaterial composite system constructs a dual sustained-release system to achieve step-by-step controlled release of antiangiogenic drugs and immune immunotherapy drugs to promote cooperative combination therapy.