Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

Combination cancer immunotherapy has shown promising potential for simultaneously eliciting antitumor immunity and modulating the immunosuppressive tumor microenvironment (ITM). However, combination immunotherapy with multiple regimens suffers from the varied chemo‐physical properties and inconsistent pharmacokinetic profiles of the different therapeutics. To achieve tumor‐specific codelivery of the immune modulators, an indocyanine green (ICG)‐templated self‐assembly strategy for preparing dual drug‐loaded two‐in‐one nanomedicine is reported. ICG‐templated self‐assembly of paclitaxel (PTX) nanoparticles (ISPN), and the application of ISPN for combination immunotherapy of the triple negative breast cancer (TNBC) are demonstrated. The ISPN show satisfied colloidal stability and high efficacy for tumor‐specific codelivery of ICG and PTX through the enhanced tumor permeability and retention effect. Upon laser irradiation, the ICG component of ISPN highly efficiently induces immunogenic cell death of the tumor cells via activating antitumor immune response through photodynamic therapy. Meanwhile, PTX delivered by ISPN suppresses the regulatory T lymphocytes (T_regs) to combat ITM. The combination treatment of TNBC with ISPN and αPD‐L1‐medaited immune checkpoint blockade therapy displays a synergistic effect on tumor regression, metastasis inhibition, and recurrence prevention. Overall, the ICG‐templated nanomedicine may represent a robust nanoplatform for combination immunotherapy.     

Size/Charge Changeable Acidity‐Responsive Micelleplex for Photodynamic‐Improved PD‐L1 Immunotherapy with Enhanced Tumor Penetration

The checkpoint blockade‐based immunotherapy has recently emerged as a promising approach for tumor treatment, but its clinical implementation has been impeded by poor tumor penetration of the nanocarriers and activation of antitumor immune response. To overcome the obstacles, a tumor acidity‐responsive micellar nanocomplex co‐loaded with programmed death‐ligand 1 (PD‐L1)‐blockade siRNA and mitochondrion‐targeting photosensitizer for the synergistic integration of photodynamic therapy and immunotherapy is reported in the present study. The nanosystem is coated with long‐circulating polyethylene glycol (PEG) shells, which can be shed in response to the weakly acidic tumor microenvironment and lead to significant size reduction and increasing positive charge. These transitions facilitate penetration and uptake of nanocarriers against tumors. Subsequently, under the mild acidic endo/lysosome condition, the micellar nanocomplexes are rapidly protonated and disintegrated to release the PD‐L1‐blockade siRNA and photosensitizer through sponge effect. Results from in vitro and in vivo experiments collectively reveal that the nanosystem efficiently activates a photodynamic therapy‐induced immune response and silences immune resistance mediated by the checkpoint gene PD‐L1. In consequence, melanoma growth is inhibited and the recurrence rate is reduced via triggering systemic antitumor immune responses. This study offers an alternative strategy for the development of efficient antitumor immune therapy.     

Toward Biomaterials for Enhancing Immune Checkpoint Blockade Therapy

Despite the remarkable progress in immune checkpoint blockade (ICB) therapy for cancer treatment, low objective response and immune‐related side effects (immune‐related adverse events, irAEs) limit the further development of ICBs. To address these challenges and enhance the efficiency of cancer immunotherapy, the emerging interest has focused on manipulating biomaterials to form innovational drug delivery systems that are necessary to effectively deliver immune checkpoint inhibitors. Such biomaterial‐based strategies can improve accumulation, control release, and enhance retention of checkpoint inhibitors within target locations while simultaneously reducing drug exposure for off‐target tissues, thereby optimizing both the efficacy and safety. In addition, with the assistance of biomaterials, combinations of ICB and conventional treatment strategies including chemotherapy, radiotherapy, and phototherapy are designed to further enhance the response rate of ICB. This review focuses on the latest reports on engineering biomaterials to improve the antitumor efficiency of ICB, with stress on antibody‐, gene‐, and trap protein–based immune checkpoint blockade strategies and their combinations with conventional therapies. Challenges and future trends in engineering biomaterials to modulate immune checkpoint therapy are discussed.     

Ternary Regulation of Tumor Microenvironment by Heparanase-Sensitive Micelle-Loaded Monocytes Improves Chemo-Immunotherapy of Metastatic Breast Cancer

Tumor immunotherapy approaches such as programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) checkpoint blockade and indoleamine 2,3-dioxygenase (IDO) inhibition are proven to promote immune response against tumors. Unfortunately, their positive response rates are unsatisfactory due to complicated immunosuppressive mechanisms in the tumor microenvironment, which can probably be rescued by integrating multiple immunoregulators and chemotherapeutic agents together. To improve the combination therapy of metastatic breast cancer, a ternary heparanase (Hpa)-sensitive micelle-loaded monocyte delivery system, termed as HDNH@MC, is designed, exploiting the capacity of Ly6C^hi monocytes to be recruited to tumor sites and the overexpression of Hpa in tumors. The prodrugs of the chemotherapeutic agent docetaxel and IDO inhibitor NLG919 are synthesized by conjugating them on the substrate of Hpa, heparan sulfate. Then the PD-1/PD-L1 inhibitor HY19991-encapsulating prodrug micelle@Ly6C^hi monocyte system is prepared. HNDH@MC elevates drug concentrations and relieves immunosuppression in tumors of 4T1 breast carcinomas mice model, thus enhancing the infiltration and activity of CD8⁺ T cells and presenting significant anti-cancer effect. The lung metastasis is suppressed and the survival of mice is prolonged. HNDH@MC will be a promising option for treating metastatic breast cancer by synergy of tumor-targeting chemotherapy and immunotherapy.     

Nanoagonist-Mediated GSDME-Dependent Pyroptosis Remodels the Inflammatory Microenvironment for Tumor Photoimmunotherapy

Immunotherapy, especially immune checkpoint blockade (ICB) antibody immunotherapy, has revolutionized the treatment ways of cancers and provided remarkable clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors with an immune-excluded or immune-suppressed phenotype is dismal due to the lack or paucity of immune infiltration in the tumor microenvironment. Herein, an emerging photoimmunotherapy based on remodeling the inflammatory microenvironment is reported, ascribed to nanoagonist-mediated gasdermin E (GSDME)-dependent pyroptosis and providing positive feedback to activate anti-PD-1 immunotherapy. An iridium-based photosensitizer (IrP) carrying methyltransferase inhibitor RG108 (R@IrP) lead to rapid cell pyroptosis via the caspase-3/GSDME pathway under the light activation. Furthermore, light-elicited pyroptosis synergized with anti-PD-1 to induce anti-tumor photoimmunotherapy. The pro-inflammatory factors released by pyroptotic cells remodel the inflammatory microenvironment and recruit immune cells to kill tumor cells, resulting in CD8⁺ cytotoxic T lymphocytes activation, PD-1 expression enhancement, and dendritic cell slightly maturation. Collectively, these findings present a synergistic strategy of photoimmunotherapy, that is, turning immunological cold tumors into hot tumors that can respond to anti-PD-1-based immunotherapy via precise pathway regulation.     

Two-Photon Absorption Induced Cancer Immunotherapy Using Covalent Organic Frameworks

Immune checkpoint blockade therapy is revolutionizing the traditional treatment model of multiple tumor types, but remains ineffective for a large subset of patients. Photodynamic therapy (PDT) has been shown to induce cancer cell death and provoke an immune response, and may represent a potential strategy to synergize with immune checkpoint blockade therapy. However, the limited tissue penetration of exciting light for conventional PDT largely hinders its application in the clinic and its further combination with immunotherapy. Here, a serrated packing covalent organic framework (COF), COF-606, with excellent two-photon absorption (2PA) property and photostability, largely avoids aggregation-caused quenching, therefore offering high reactive oxygen species (ROS) generation efficiency; it is used as a 2PA photosensitizer for PDT in deep tumor tissue. COF-606 induced PDT is shown to be efficient in inducing immunogenic cell death, provoking an immune response and normalizing the immunosuppressive status for the first time. This makes it possible to combine 2PA induced PDT using COF with programmed cell death protein 1 immune checkpoint blockade therapy. Such combination leads to strong abscopal tumor-inhibiting efficiency and long-lasting immune memory effects, standing as a promising combinatorial therapeutic strategy for cancer treatment.     

A Near-Infrared Light-Responsive ROS Cascade Nanoplatform for Synergistic Therapy Potentiating Antitumor Immune Responses

Tumor occurrence is closely related to the unlimited proliferation and the evasion of the immune surveillance. However, it remains a challenge to kill tumor cells and simultaneously activate antitumor immunity upon spatially localized external stimuli. Herein, a robust tumor synergistic therapeutic nanoplatform is designed in combination with dual photosensitizers-loaded upconversion nanoparticles (UCNPs) and ferric-tannic acid (FeTA) nanocomplex. Dual photosensitizers-loaded UCNPs can induce photodynamic therapy (PDT) effect by generation of cytotoxic reactive oxygen species (ROS) on demand under near-infrared (NIR) light irradiation. FeTA can robustly respond to acidic tumor microenvironment to produce Fe²⁺ and subsequently induce chemodynamic therapy (CDT) by reacting with H₂O₂ in the tumor microenvironment. More importantly, the CDT/PDT synergy can not only exhibit significant antitumor ability but also induce ROS cascade to evoke immunogenic cell death. It increases tumor immunogenicity and promotes immune cell infiltration at tumor sites allowing further introduction of systemic immunotherapy responsiveness to inhibit the primary and distant tumor growth. This study provides a potential tumor microenvironment-responsive nanoplatform for imaging-guided diagnosis and combined CDT/PDT with improved immunotherapy responses and an external NIR-light control of photoactivation.     

Sono/Photodynamic Nanomedicine-Elicited Cancer Immunotherapy

Immunotherapy (e.g., cancer vaccines and checkpoint blockades), harnessing the host immune system to recognize and eradicate tumors, has emerged as one of the most potent cancer therapies. The clinical applications of cancer immunotherapies, however, have been limited by their low response rates and immune-related adverse effects. In recent years, sono/photodynamic nanomedicines (SPNs) have received increasing attention for cancer therapy since they have been reported to mediate enhanced immunotherapy by generating reactive oxygen species under site-specific exposure to exogenous energy sources. In particular, SPNs are capable of eliciting immunogenic cancer cell death, leading to the release of tumor-associated antigens and damage-associated molecular patterns. This allows for the maturation of antigen-presenting cells, thus eliminating disseminated or metastatic tumor cells by cytotoxic CD8⁺ T cells. Such immunostimulatory features of SPNs provide opportunities to enhance therapeutic potential by amplifying anticancer immunity when combined with conventional immunotherapeutics, including immune checkpoint inhibitors. This review elaborates on the recent strategies and efforts undertaken by researchers to enhance SPN-elicited cancer immunotherapy. The challenging issues and opportunities for SPNs in the activation of innate or adaptive immune responses and regulation of the tumor immunosuppressive microenvironment are also described.     

Combining Photothermal-Photodynamic Therapy Mediated by Nanomaterials with Immune Checkpoint Blockade for Metastatic Cancer Treatment and Creation of Immune Memory

The pursuit of effective treatments for metastatic cancer is still one of the most intensive areas of research in the biomedical field. In a not-so-distant past, the scientific community has witnessed the rise of immunotherapy based on immune checkpoint inhibitors (ICIs). This therapeutic modality intends to abolish immunosuppressive interactions, re-establishing T cell responses against metastasized cancer cells. Despite the initial enthusiasm, the ICIs were later found to be associated with low clinical therapeutic outcomes and immune-related side effects. To address these limitations, researchers are exploring the combination of ICIs with nanomaterial-mediated phototherapies. These nanomaterials can accumulate within the tumor and produce, upon interaction with light, a temperature increase (photothermal therapy) and/or reactive oxygen species (photodynamic therapy), causing damage to cancer cells. Importantly, these photothermal-photodynamic effects can pave the way for an enhanced ICI-based immunotherapy by inducing the release of tumor-associated antigens and danger-associated molecular patterns, as well as by relieving tumor hypoxia and triggering a pro-inflammatory response. This progress report analyses the potential of nanomaterial-mediated photothermal-photodynamic therapy in combination with ICIs, focusing on their ability to modulate T cell populations leading to an anti-metastatic abscopal effect and on their capacity to generate immune memory that prevents tumor recurrence.     

Hypoxia-Responsive Nanoscale Coordination Polymer Enhances the Crosstalk Between Ferroptosis and Immunotherapy

The immunosuppressive tumor microenvironment (TME) severely limits the clinical applications of cancer immunotherapy. Herein, a hypoxia-responsive delivery system is constructed simply by coordinating ferric (Fe³⁺) with mitoxantrone (MTO), sulfasalazine (SAS), and hypoxia-sensitive dopamine derivative of polyethylene glycol (PEG) using “one-pot” reaction for the “closed-loop” synergistic enhancement of ferroptosis and immunotherapy. Hypoxia-sensitive PEG ensures the integrity of delivery system in circulation to prevent the premature leakage of drugs, and the detachment of PEG in the interior hypoxic TME can facilitate the deep penetration and the subsequent tumor uptake. The released iron and MTO induce the generation of reactive oxygen species (ROS), while SAS inhibits the elimination of lipid peroxides by inhibiting SLC7A11 subunit of glutamate-cystine antiporter, which synergistically induces immunogenic ferroptosis to promote dendritic cells maturation and T cells activation. The activated CD8⁺ T cells then release interferon γ (IFN-γ) and in turn enhance ferroptosis by downregulating the expression of SLC7A11. As a result, the “closed-loop” synergistic enhancement between ferroptosis and immunotherapy significantly prevents tumor growth and prolonged survival time of tumor-bearing mice with no obvious systemic toxicity. The excellent therapeutic effect together with the scalable synthesis and controllable quality will promise its translation to clinic as a novel immunotherapy.     

Photostable Iodinated Silica/Porphyrin Hybrid Nanoparticles with Heavy‐Atom Effect for Wide‐Field Photodynamic/Photothermal Therapy Using Single Light Source

Physical therapies including photodynamic therapy (PDT) and photothermal therapy (PTT) can be effective against diseases that are resistant to chemotherapy and remain as incurable malignancies (for example, multiple myeloma). In this study, to enhance the treatment efficacy for multiple myeloma using the synergetic effect brought about by combining PDT and PTT, iodinated silica/porphyrin hybrid nanoparticles (ISP HNPs) with high photostability are developed. They can generate both ¹O₂ and heat with irradiation from a light‐emitting diode (LED), acting as photosensitizers for PDT/PTT combination treatment. ISP HNPs exhibit the external heavy atom effect, which significantly improves both the quantum yield for ¹O₂ generation and the light‐to‐heat conversion efficiency. The in vivo fluorescence imaging demonstrates that ISP HNPs, modified with folic acid and polyethylene glycol (FA‐PEG‐ISP HNPs), locally accumulate in the tumor after 18 h of their intravenous injection into tumor‐bearing mice. The LED irradiation on the tumor area of the mice injected with FA‐PEG‐ISP HNPs causes necrosis of the tumor tissues, resulting in the inhibition of tumor growth and an improvement in the survival rate.     

Bioresponsive Self-Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune-Related Adverse Events in Tumor Immunotherapy

Despite the immense potential of immune checkpoint blockade (ICB) therapy in tumor treatment, its widespread clinical application is currently limited by unsatisfactory curative effect and off-target adverse effect. Herein, an injectable sericin (SS)/silk fibroin (SF) recombinant hydrogel, termed SF-SS-SMC hydrogel, is developed to enable local delivery of anti-CD47 antibody (α CD47). The hydrogel displays self-reinforcement in high H₂O₂ concentration of tumor microenvironment (TME), as the SS/Fe²⁺ supramolecular nanocomplex (SS-SMC) inside the hydrogel converts H₂O₂ to reactive oxygen species (ROS), further triggering additional crosslinking among the SF polymers. Therefore, the SF-SS-SMC hydrogel has an in vivo retention time longer than 21 days and acts as a reservoir for the long-term sustained release of α CD47. More importantly, the SF-SS-SMC hydrogel itself efficiently regulates the remodeling of a protumor immunosuppressive TME to an antitumoral TME through switching of tumor-associated macrophages from an anti-inflammatory M2 phenotype to a proinflammatory M1 phenotype without additional drugs. Based on the combined effect of sustained α CD47 release and TME reprogramming, the SF-SS-SMC hydrogel has satisfactory immunotherapeutic effects in the treatment of local, abscopal, remitting, and metastatic tumors. Further advantages, including low cost of production, simple fabrication, and ease of use, make it promising for commercial mass production.     

Schottky Heterojunction Realizes In Situ Vaccine-Like Antitumor Efficacy and Microenvironment Remodeling Upon Near-Infrared Laser Response in Cold Tumors

Cold tumor is one of the most refractory tumors due to its low immunogenicity and absence of T cell infiltration. The immunotherapeutic effect of near-infrared (NIR) responsive nanomaterials on tumors is far from satisfactory. Herein, ultrasmall γ-MnO₂ nanodots are anchored on the intrinsic metallic Ti₃C₂(OH)₂, modified with bovine serum albumin, to realize a Schottky heterojunction (labeled as TC-MnO₂@BSA), which can be utilized to reshape the cold tumor microenvironment (TME) through in situ vaccine-like antitumor effect. The Schottky heterojunction endows TC-MnO₂@BSA with improved photothermal conversion and reactive oxygen species (ROS) generation. Excess ROS and heat lead to tumor immunogenic death (ICD) and abundant damaged double-strain DNA releasing into TME, coordinated with TC-MnO₂@BSA-derived Mn²⁺, magnifying the cGAS-STING signaling pathway, eventually promoting antigen presentation of dendritic cells and infiltration of T cells. Such a NIR-activated nanovaccine can achieve complete ablation of tumors while robust activating systemic antitumor immune response. Furthermore, it inhibits the growth of abscopal tumors through dramatically “heating” their cold TME. This work introduces a universal strategy to magnify the photothermal and immune adjuvant effect through the gain of Schottky heterostructure, as a novel paradigm to construct the multifunctional in situ nanovaccine.     

Robust Nanovaccine Based on Polydopamine-Coated Mesoporous Silica Nanoparticles for Effective Photothermal-Immunotherapy Against Melanoma

Nanoparticle-based combination therapy strategy of photothermal therapy (PTT) and immunotherapy is an attractive cancer treatment for ablating tumors and eliciting host immune responses. However, this strategy is often hampered by tedious treatment process and limited immune response, and usually needs to be combined with checkpoint blockades to enhance therapeutic effect. Herein, a nanoplatform with mesoporous silica nanoparticles (MSNs) as a vector, which integrated photothermal agent polydopamine (PDA), model antigen ovalbumin (OVA), and antigen release promoter ammonium bicarbonate (ABC) in an easy way for melanoma PTT-immunotherapy is designed. The formulated MSNs-ABC@PDA-OVA nanovaccine exhibits excellent photothermal properties and effectively eliminates primary tumors. Under laser irradiation, the MSNs-ABC@PDA-OVA nanovaccine realizes rapid antigen release and endosome escape, enhances dendritic cells activation and maturation, facilitates migration to tumor-draining lymph nodes, and induces robust antitumor immune responses. Impressively, single injection of MSNs-ABC@PDA-OVA combines with single round of PTT successfully eradicates melanoma tumors with a cure rate of 75% and generates strong immunological memory to inhibit tumor recurrence and lung metastasis. Hence, the research offers a simple and promising strategy of synergistic PTT-immunotherapy to effectively treat cancer.     

High‐Security Nanocluster for Switching Photodynamic Combining Photothermal and Acid‐Induced Drug Compliance Therapy Guided by Multimodal Active‐Targeting Imaging

High‐security nanoplatform with enhanced therapy compliance is extremely promising for tumor. Herein, using a simple and high‐efficient self‐assembly method, a novel active‐targeting nanocluster probe, namely, Ag₂S/chlorin e6 (Ce6)/DOX@DSPE‐mPEG₂₀₀₀‐folate (ACD‐FA) is synthesized. Experiments indicate that ACD‐FA is capable of specifically labeling tumor and guiding targeting ablation of the tumor via precise positioning from fluorescence and photoacoustic imaging. Importantly, the probe is endowed with a photodynamic “on‐off” effect, that is, Ag₂S could effectively quench the fluorescence of chlorin e6 (89.5%) and inhibit release of ¹O₂ (92.7%), which is conducive to avoid unwanted phototoxicity during transhipment in the body, and only after nanocluster endocytosed by tumor cells could release Ce6 to produce ¹O₂. Moreover, ACD‐FA also achieves excellent acid‐responsive drug release, and exhibits eminent chemo‐photothermal and photodynamic effects upon laser irradiation. Compared with single or two treatment combining modalities, ACD‐FA could provide the best cancer therapeutic effect with a relatively low dose, because it made the most of combined effect from chemo‐photothermal and controlled photodynamic therapy, and significantly improves the drug compliance. Besides, the active‐targeting nanocluster notably reduces nonspecific toxicity of both doxorubicin and chlorin e6. Together, this study demonstrates the potency of a newly designed nanocluster for nonradioactive concomitant therapy with precise tumor‐targeting capability.     

MAPK‐Targeted Drug Delivered by a pH‐Sensitive MSNP Nanocarrier Synergizes with PD‐1 Blockade in Melanoma without T‐Cell Suppression

The combination of BRAF/MEK‐targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK‐inhibitor‐induced T‐cell toxicity impedes effective cooperation. In this experiment, a pH‐responsive on‐demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein‐isothiocyanate‐loaded MSNP can be specifically delivered into tumor cells rather than T‐cells. MEK‐inhibitor‐loaded MSNP avoids proliferative and functional inhibitions of T‐cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK‐inhibitor‐induced suppression of activated CD8⁺ T‐cells, and enhances the secretion of INF‐γ and IL‐2. The combination of BRAF inhibitor plus MSNP‐loaded MEK inhibitor and anti‐PD‐1 antibody synergistically inhibits tumor growth via promoting robust immune‐related antitumor response. This work provides a novel and generalized framework for combining T‐cell‐impaired targeted therapy and immune checkpoint blockade by using a nanoparticle‐based delivery system.     

Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

The application of combinational therapy makes up for the limitation of monotherapy and achieves superior treatment against cancer. However, the combinational therapy remains restricted by the poor tumor‐specific delivery and the abscopal effect. Herein, reactive oxygen species (ROS)‐responsive PEGylated bilirubin nanoparticles (BRNPs) are developed to encapsulate two glutathione‐activatable drugs, including dimer‐7‐ethyl‐10‐hydroxycamptothecin (d‐SN38) and dimer‐lonidamine (d‐LND). Dimerization of the drugs significantly increases the drug loading capacity and the encapsulation efficiency of nanoparticles. With the assistance of iRGD peptide (cRGDKGPDC), the cellular uptake of BRNPs is more than double when compared with the control. In response to high levels of intracellular ROS, d‐SN38 and d‐LND are rapidly released from nanoparticles (SL@BRNPs). Furthermore, the pharmacodynamic experiments verify combining SL@BRNPs with anti‐PD‐L1 antibody greatly inhibits the primary tumor of breast cancer, improves CD8+ T cells levels, and CD8+ T cells/Tregs ratios in the tumor. Additionally, it shows high immune memory effect and can prevent the growth of lung metastasis. Taken together, the strategy pioneers a new way for the rational design of nanoassemblies through the combination of activatable drug dimers and stimuli‐responsive drug release, and a successful application of novel drug delivery systems in combination with the immune checkpoint blockade antibody.     

Engineering a Therapy‐Induced “Immunogenic Cancer Cell Death” Amplifier to Boost Systemic Tumor Elimination

Immunogenic cancer cell death (ICD) is drawing worldwide attention as it allows dying cancer cells to regulate the host's anti‐tumor immune system and awaken immunosurveillance. Thus, effectively activating therapy‐induced ICD is of great clinical significance to raise systemic anti‐tumor immunity and eradicate post‐treatment/abscopal cancer tissues. Enhanced cytotoxic reactive oxygen species (ROS) generation in cancer therapy has been positively correlated to ICD induction, which inspires design of a therapy‐induced ICD amplifier. The nanohybrid amplifier (FeOOH@STA/Cu‐LDH) is devised based on Cu‐containing layered double hydroxide (Cu‐LDH), incorporating ROS inducer (FeOOH nanodots), ROS generation booster (Cu‐LDH for photothermal therapy), and heat shock protein inhibitor (STA). Treating 4T1 tumor cells with this amplifier translocates calreticulins (CRT, one of main ICD signals) on the surface of dying cancer cells, which achieves the maximum at fever‐type temperature (40–42 °C). To demonstrate immunotherapeutic efficacy of this nanohybrid, 4T1 tumor‐bearing mouse model is established with primary and abscopal tumors. Significantly, only one treatment with the ICD amplifier eradicates the primary tumor and inhibits the abscopal tumor growth upon fever‐type heating and induces more cytotoxic T lymphocytes in abscopal tumors and spleens after treatment for 1 week. This research thus provides a new insight into nanomaterial‐mediated tumor immunotherapy.     

Reversing Immunosuppression in Hypoxic and Immune-Cold Tumors with Ultrathin Oxygen Self-Supplementing Polymer Nanosheets under Near Infrared Light Irradiation

Solid tumors are characterized by a hypoxic and immunologically “cold” microenvironment that dramatically limits the therapeutic outcomes of immunotherapy. Thus, strategies and materials that are capable of reversing immunosuppression in immune-cold tumors are highly desired. Herein, it is reported that oxygen (O₂) self-supplementing conjugated microporous polymer nanosheets can be utilized to elicit a robust antitumor T cell immune response in the hypoxic and immunosuppressive tumor microenvironment. The ultrathin nanosheets can generate O₂ through the water splitting reaction and produce massive reactive oxygen species (ROS) under near infrared light irradiation. Meanwhile, the unique photothermal property of the conjugated polymer nanosheets generates hyperthermia under irradiation. Consequently, they are able to maximize the immunogenic cell death (ICD) performance by inducing adequate damage-related molecular patterns in hypoxic tumors. Other than fostering T cell infiltration by the elicited ICD, the loaded indoleamine 2,3-dioxygenase in nanosheets can reverse the immunosuppression and empower ICD effect for efficient T cells priming. In vivo experiments conclusively prove that the designed polymer nanosheets exhibit great potential for tumor eradication, metastasis prevention, as well as long-term survival. Such a photocatalytic platform opens up new paths for reversing immunosuppression in immune-cold tumors and broadens the application of polymer-based nanosheets for cancer therapy.