Ferroptosis and Pyroptosis Co-Activated Nanomodulator for “Cold” Tumor Immunotherapy and Lung Metastasis Inhibition

Immune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., “cold” tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on “immunosilent” apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH-responsive nanomodulator is reported that can reverse the immunosuppressive TME for “cold” tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA-approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide-doped organosilica hybrid micelles, where SAS and DOX are released through the GSH-stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor-associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand-1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator-induced non-apoptotic death provides a new promising paradigm for ICB therapy.     

Metabolic Regulation of Tumor Microenvironment with Biohybrid Bacterial Bioreactor for Enhanced Cancer Chemo-Immunotherapy

Immunogenic cell death (ICD) induced by specific chemotherapeutic agents is often hampered by the immunosuppressive tumor microenvironment (TME). Here, a bacterial bioreactor E@Fe-DOX, is developed, to enhance ICD-mediated antitumor immunity by in situ manipulation of tumor metabolism-immune interactions. The E@Fe-DOX bioreactor is constructed by depositing doxorubicin-loaded iron-polyphenol nanoparticles on Eubacterium hallii, which can specifically target hypoxic tumor regions and release doxorubicin and Fe³⁺ to induce ICD. In addition, Eubacterium hallii can continuously convert intratumoral lactate to butyrate, which inhibits the polarization of pro-tumoral M2-like macrophages and improves the function of tumor-infiltrating cytotoxic T cells. Furthermore, E@Fe-DOX promotes the formation of immune cell-aggregated tertiary lymph structures (TLS) to augment ICD-induced antitumor immunity. In murine tumor models, E@Fe-DOX significantly inhibits tumor growth and enhances immune checkpoint blockade (ICB) therapy. Overall, the developed living biomaterial offers a promising strategy to potentiate cancer chemo-immunotherapy by continuously regulating the intratumoral immuno-metabolic microenvironment.     

Polysaccharide Nanodonuts for Photochemotherapy-Amplified Immunogenic Cell Death to Potentiate Systemic Antitumor Immunity Against Hepatocellular Carcinoma

Immunotherapy shows great promise in the treatment of hepatocellular carcinoma (HCC), however, the low response rate of HCC patients to immunotherapy caused by inadequately immunogenic and immunosuppressive tumor microenvironment (TME) is a huge challenge. Herein, a donut-like multifunctional polysaccharide nanoplatform (GH-PID) is constructed from doxorubicin/aldehyde hyaluronan nanoring, indocyanine green/hydroxyethyl chitosan nanocomplex, and HCC-bitargeted galactosamine-hyaluronan conjugate via a facile self-assembly process. The GH-PID nanodonuts exhibit excellent HCC-targeted ability and synergetic photochemotherapy effect with a coefficient index of about 0.44. Moreover, near infrared laser-irradiated GH-PID nanodonuts show robust therapeutic efficacy in HCC mouse models by virtue of photochemotherapy-augmented immunogenic cell death (ICD) effect. The remarkable ICD in combination with programmed death-1 antibody efficiently eradicates primary tumors and inhibits distant tumor growth and lung metastasis of HCC by maturing dendritic cells, increasing CD8⁺ T cell infiltration, suppressing the expansion and trafficking of immunosuppressive myeloid-derived suppressor cells, and ameliorating immunosuppressive TME. This study provides a facile and versatile strategy to construct polysaccharide nanodonuts integrating multifunctionality and highly efficient HCC-targeted ability, and the nanodonuts-based ICD inducer holds great promise for potentiating systemic antitumor immunity and programmed death-1/programmed death-ligand 1 blockade efficacy.     

Engineered Oxygen Factories Synergize with STING Agonist to Remodel Tumor Microenvironment for Cancer Immunotherapy

Immunotherapy is a revolutionary achievement in cancer treatment. However, inadequate immune cells infiltration in tumor microenvironment (TME) always leads to treatment failure. Moreover, hypoxic TME hampers normal functions of immune cells. Here, it is found that hypoxia suppresses the STING signaling and immune cells activation in the work. Remodeling tumor immune microenvironment and relieving hypoxia are thus essential for enhancing immunotherapy efficiency. Herein, a spirulina platensis (SP)-based magnetic biohybrid system is constructed as an oxygen factory and loaded with stimulator of interferon genes (STING) agonist ADU-S100 (ADU@Fe-SP) for tumor immunotherapy. Magnet-guided biohybrid SP can actively target tumor tissues and produce oxygen in situ through photosynthesis, which reverses the hypoxic TME and facilitates the function of immune cells. Besides, the targeted delivery of ADU-S100 can activate the STING/TBK1/IRF3 signaling and boost cytokines production in tumor and innate immune cells. The ADU@Fe-SP system thus induces efficient immune cells infiltration in TME, which efficiently inhibits tumor progression and significantly enhances anti-PD-1 therapy efficiency in SCC VII-bearing tumor xenograft. ADU@Fe-SP exerts antitumor effect in a STING-dependent manner by in vivo STING-knockout mice model. The efficiency of this immunotherapy strategy is also demonstrated in patient-derived xenograft model originating from oral cancer, showing great clinical potential.     

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.     

An Integrated Nanoaircraft Carrier Modulating Antitumor Immunity to Enhance Immune Checkpoint Blockade Therapy

Immune checkpoint blockade (ICB) therapy revolutionizes cancer therapeutics. However, the effectiveness of ICB therapy is restricted. Focusing on the tumor itself and the immune system, an integrated nanoaircraft carrier that coloaded three therapeutic agents (NNG/OTC) to eradicate tumor cells, enhance T-cells intratumoral infiltration, and relieve the inhibition of tumor immunosuppressive microenvironment (TIM) is designed. First, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is used to combine with oxaliplatin for reducing tumor burden. Second, oxaliplatin is used to elicit immunogenic cell death and combine with cytosine-phosphate-guanine (CpG) to promote dendritic cells maturation, ultimately increasing T-cells intratumoral infiltration. Third, CpG is further used to repolarize M2 type of tumor-associated macrophages, thus reversing immunosuppression of TIM. The nanoaircraft carrier can effectively arrive at the tumor site and detach small-sized nanoparticles under a high concentration of matrix metalloproteinase-2, which promotes deep tumor penetration. Under the mediation of targeting ligands, three therapeutic agents loaded in small-sized nanoparticles could be launched to their target cells. NNG/OTC modulates the antitumor immunity and exhibits excellent tumor inhibition when in combination with ICB therapy, indicating the increased response of ICB therapy. Collectively, NNG/OTC can co-deliver various drugs with different physicochemical properties and provide a promising strategy for enhancing ICB therapy.     

Synergy of Immunostimulatory Genetherapy with Immune Checkpoint Blockade Motivates Immune Response to Eliminate Cancer

Normalizing the tumor-induced immune deficiency in the immunosuppressive tumor microenvironment (TME) through increasing the efficient infiltration and activation of antitumoral immunity in TME is the core of promising immunotherapy. Herein, a Cyclo(Arg-Gly-Asp-d -Phe-Lys) (RGD) peptides-modified combinatorial immunotherapy system based on the self-assembly of the nanoparticles named RGD-DMA composed of RGD-PEG-PLA, methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) is used to codeliver the immunostimulatory chemokine CCL19-encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD-L1 inhibitor (BMS-1). The RGD-DMA/pCCL19-BMS-1 system not only exhibited significant inhibition of tumor progression but also induced locally high concentrations of immunostimulatory cytokines at tumor sites without causing an obviously systemic inflammatory response. The immunosuppressive TME is efficaciously reshaped by the coadministration of RGD-DMA/pCCL19 and BMS-1, as indicated by the activated T lymphocytes, increased intratumoral-infiltration of mature dendritic cells (DCs), and the repolarization of macrophages from pro-tumoral M2-phenotype toward tumoricidal M1-phenotype. The upregulated PD-L1 expression at tumor sites caused by the increased IFN-γ levels after immunostimulatory gene therapy further demonstrated the synergistic effects of BMS-1 in counteracting the inhibitory role of PD-L1 expression in antitumor immunity. Therefore, the combination of immunostimulating therapy and immune checkpoint inhibitor that synergistically target multiple immune regulatory pathways demonstrates significant potential as a novel immunotherapy approach.     

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.     

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.     

Design of Mitoxantrone-Loaded Biomimetic Nanocarrier with Sequential Photothermal/Photodynamic/Chemotherapy Effect for Synergized Immunotherapy

Metastatic triple-negative breast cancer (TNBC) has a poor prognosis and high mortality with no effective treatment options, and immunotherapy is highly anticipated as a potential treatment but is limited by the lack of tumor-infiltrating T lymphocytes in TNBC. Herein, red blood cell (RBC) membrane-camouflaged polyphosphoester (PPE) nanoparticles (RBC@PPE_MTO/PFA) are prepared as the nanocarriers of mitoxantrone (MTO) and perfluoroalkane (PFA) for synergized immunotherapy. The encapsulated MTO can generate heat and reactive oxygen species (ROS) to achieve photothermal and photodynamic therapy; moreover, ROS further triggers the self-accelerating release of MTO from the ROS-sensitive PPE core to enable chemotherapy. The RBC@PPE_MTO/PFA-mediated sequential photothermal/photodynamic/chemotherapy efficiently promotes the infiltration of CD8⁺ T cells into TNBC tumor tissue and synergizes the therapeutic activity of an immune checkpoint blockade antibody for metastatic TNBC treatment in distant and lung metastasis models. This biomimetic nanomedicine of MTO provides a convenient and available strategy to sensitize TNBC to immune checkpoint blockade antibody.     

Nanoparticle‐mediated HMGA1 Silencing Promotes Lymphocyte Infiltration and Boosts Checkpoint Blockade Immunotherapy for Cancer

For most cancer types, only a minority of cancer patients respond to checkpoint inhibition therapy. T lymphocyte infiltration is critically important for checkpoint blockade immunotherapy. High expression of high mobility group protein A1 (HMGA1) is observed in rapidly proliferating neoplastic cells, and is reported to contribute to the immunosuppressive microenvironment in the tumor. Herein, whether the silencing of HMGA1 using a nanoparticle (NP) approach could promote T lymphocyte infiltration into the tumor, and sensitize tumors to checkpoint inhibitor therapy in several orthotopic murine cancer models, which has high levels of HMGA1 but little T lymphocyte infiltration, is investigated. Selectively silencing HMGA1 using a lipid‐protamine‐hyaluronic acid‐siHMGA1 (LPH‐siHMGA1) NP system greatly enhances the lymphocyte infiltration in the tumor. Furthermore, the combination of LPH‐siHMGA1 and a locally expressed PD‐L1 inhibitor system, a lipid‐protamine‐DNA NP loaded with plasmid encoding the PD‐L1 trap fusion protein, significantly inhibits the tumor growth and prolonged survival. LPH‐siHMGA1 also decreased the content of stem cells in the tumor. These findings highlight the potential of targeting HMGA1, especially using a nano approach, in the combination with cancer immunotherapy, and provide a strategy for broadening the application and enhancing the efficacy of checkpoint inhibitors.     

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.     

Oxygen-Evolving Manganese Ferrite Nanovesicles for Hypoxia-Responsive Drug Delivery and Enhanced Cancer Chemoimmunotherapy

Immunological tolerance induced by the hypoxic tumor microenvironment has been a major challenge for current immune checkpoint blockade therapies. Here, a hypoxia-responsive drug delivery nanoplatform is reported to promote chemoimmunotherapy of cancer by overcoming the hypoxia-induced immunological tolerance of tumors. The nanovesicles are assembled from manganese ferrite nanoparticles (MFNs) grafted with hypoxia-responsive amphiphilic polymers as the membrane, with doxorubicin hydrochloride (Dox) loaded in the aqueous cavities. Under hypoxic conditions in tumors, the nanovesicles can rapidly dissociate into individual MFNs to release Dox and induce decomposition of tumor endogenous H₂O₂ for tumor hypoxia relief. As a result, the Dox-loaded nanovesicles display remarkable suppression of primary tumor growth in combination with αPD-L1-mediated checkpoint blockade therapy. Furthermore, the modulation of the hypoxic tumor microenvironment facilitates a long-lasting immunological memory effect to prevent tumor recurrence and metastasis. Therefore, this hypoxia-responsive nanoplatform presents a potential strategy for both local tumor treatment and long-term protection against tumor recurrence.     

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.     

In Situ Formed Fibrin Scaffold with Cyclophosphamide to Synergize with Immune Checkpoint Blockade for Inhibition of Cancer Recurrence after Surgery

Unsatisfied cytoreductive surgery predicts worse clinical outcomes. Previous studies have found that cyclophosphamide (CTX) is a rhythmic immune modulator that can target suppressive regulatory immune cells and meanwhile enhance effector cells. Here, a therapeutic scaffold is engineered based on a fibrin hydrogel to codeliver CTX and anti‐PD‐L1 antibody (aPDL1) for the prevention of cancer recurrence postsurgery. It is demonstrated that the sequential release of CTX and aPDL1 from the fibrin hydrogel can lead to selective depletion of regulatory T cells (Treg) in the residual tumor, which would then synergize the immune checkpoint blockade therapy. The therapeutic benefit is demonstrated in an orthotopic breast tumor and an orthotopic ovarian tumor model after incomplete resection of primary tumors. In this work, the strategy provides a clinically valuable option for preventing cancer recurrence postsurgery.     

A Self-Enhancing Nanoreactor Reinforces Radioimmunotherapy by Reprogramming Nutrients and Redox Metabolisms

Altered metabolism of cancer cells reshapes the unique tumor microenvironment (TME) with glucose addiction and high antioxidant levels, resulting in a strong alliance to promote tumor progression and treatment failure. Herein, a Pd/Pt/Au tri-metallic mesoporous nanoparticle coated with pH-responsive tannic acid-iron ion (Fe^IIITA) network (PdPtAu@TF) is fabricated, aiming at reinforcing radioimmunotherapy by reprogramming nutrients and redox metabolisms. PdPtAu@TF has a fine hierarchical structure and demonstrates high glucose oxidase, peroxidase-, catalase- and glutathione peroxidase-mimic activities, acting as a self-enhancing nanoreactor to consume endogenous glucose and break redox homeostasis in the harsh TME. As a result, cancer cells accelerate the uptake of lipids, especially polyunsaturated fatty acids when glucose is deficient, and then fall into lipid peroxidation-induced ferroptosis trap to sensitize radiotherapy (RT), inhibiting tumor progression. More significantly, combined treatment with PdPtAu@TF can promote the polarization of pro-inflammatory M1-type macrophages as well as inhibit the proliferation of cancer-associated fibroblasts to overcome RT-induced immunosuppression and eliminate excessive tissue fibrosis, thereby eliciting antitumor immunity and suppressing tumor metastasis. Consequently, this study describes a promising strategy to enhance the efficacy of radioimmunotherapy by reprogramming tumor nutrients and redox metabolisms, which has great potential to benefit cancer treatments.     

Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

The condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.     

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.     

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.     

Cationic Lipids-Mediated Dual-Targeting of Both Dendritic Cells and Tumor Cells for Potent Cancer Immunotherapy

Impaired antigen presentation either in dendritic cells (DCs) or tumor cells impedes the triggering of antitumor immunity or tumor cell killing, resulting in failures of multiple types of cancer immunotherapy. Herein, the strategy of using dual-targeting nanomedicines to simultaneously improve the presentation of tumor antigens by both DCs and tumor cells is proposed. It is shown that tuning of surface charge of nanoparticles (NPs) by incorporating different amounts of cationic lipids alters the in vivo NP tissue accumulation and cellular targeting profiles. NPs with moderately positive surface charge (≈20 mV) achieve efficient accumulation in tumors and lymph nodes and dual-targeting to both DCs and tumor cells. As a proof-of-concept demonstration, siRNA against YTH N6−methyladenosine RNA binding protein 1 (YTHDF1) is delivered by the dual-targeting NPs to inhibit excessive antigen degradation in both DCs and tumor cells. For DCs, YTHDF1 downregulation promotes tumor antigen cross-presentation and cross-priming of antigen-specific T cells. For tumor cells, it enhances the presentation of endogenous tumor antigens and hence improves both the recognition and killing of tumor cells by primed antigen-specific T cells. The dual-targeting nanomedicines generate efficient antitumor immunity.