Neoantigen Immunotherapeutic-Gel Combined with TIM-3 Blockade Effectively Restrains Orthotopic Hepatocellular Carcinoma Progression.

Herein, we integrate the Hepa1-6 liver cancer-specific neoantigen, toll-like receptor 9 agonist and stimulator of interferon genes agonist by silk-hydrogel package, and combine with TIM-3 blockade to elicit robust antitumor immunity for effectively suppressing orthotopic hepatocellular carcinoma (HCC) progression. Unlike intradermal injection of simple mixed components with short-term immune protection, the neoantigen immunotherapeutic-gels evoke long-term immune protection to achieve significant prophylactic and therapeutic activity against HCC through only one-shot administration without any side effects. Notably, the synergized immunotherapy by further combining NGC-gels with TIM-3 antibody significantly reduces regulatory T-cells and increases the IFN-γ and IL-12p70 levels in tumor tissues for promoting the infiltration of IFN-γ+CD8+T-cells and 41BB+CD8+T-cells to achieve complete remission (4/7) and prevent pulmonary metastasis in orthotopic HCC, and establish long-term memory against tumor rechallenge with remarkably longer survival time (180 days). Overall, this study provides an attractive and promising synergistic strategy for HCC immunotherapy with possible clinical translation prospects.

Hydroxyethyl starch-based self-reinforced nanomedicine inhibits both glutathione and thioredoxin antioxidant pathways to boost reactive oxygen species-powered immunotherapy.

The adaptive antioxidant systems of tumor cells, predominantly glutathione (GSH) and thioredoxin (TRX) networks, severely impair photodynamic therapy (PDT) potency and anti-tumor immune responses. Here, a multistage redox homeostasis nanodisruptor (Phy@HES-IR), integrated by hydroxyethyl starch (HES)-new indocyanine green (IR820) conjugates with physcion (Phy), an inhibitor of the pentose phosphate pathway (PPP), is rationally designed to achieve PDT primed cancer immunotherapy. In this nanodisruptor, Phy effectively depletes intracellular GSH of tumor cells by inhibiting 6-phosphogluconate dehydrogenase (6PGD) activity. Concurrently, it is observed for the first time that the modified IR820-NH2 molecule not only exerts PDT action but also interferes with TRX antioxidant pathway by inhibiting thioredoxin oxidase (TRXR) activity. The simultaneous weakening of two major antioxidant pathways of tumor cells is favorable to maximize the PDT efficacy induced by HES-IR conjugates. By virtue of the excellent protecting ability of the plasma expander HES, Phy@HES-IR can remain stable in the blood circulation and efficiently enrich in the tumor region. Consequently, PDT and metabolic modulation synergistically induced immunogenic cell death, which not only suppressed primary tumors but also stimulated potent anti-tumor immunity to inhibit the growth of distant tumors in 4T1 tumor-bearing mice.

Modulating tumor mechanics with nanomedicine for cancer therapy.

Over the past several decades, the importance of the tumor mechanical microenvironment (TMME) in cancer progression or cancer therapy has been recognized by researchers worldwide. The abnormal mechanical properties of tumor tissues include high mechanical stiffness, high solid stress, and high interstitial fluid pressure (IFP), which form physical barriers resulting in suboptimal treatment efficacy and resistance to different types of therapy by preventing drugs infiltrating the tumor parenchyma. Therefore, preventing or reversing the establishment of the abnormal TMME is critical for cancer therapy. Nanomedicines can enhance drug delivery by exploiting the enhanced permeability and retention (EPR) effect, so nanomedicines that target and modulate the TMME can further boost antitumor efficacy. Herein, we mainly discuss the nanomedicines that can regulate mechanical stiffness, solid stress, and IFP, with a focus on how nanomedicines change abnormal mechanical properties and facilitate drug delivery. We first introduce the formation, characterizing methods and biological effects of tumor mechanical properties. Conventional TMME modulation strategies will be briefly summarized. Then, we highlight representative nanomedicines capable of modulating the TMME for augmented cancer therapy. Finally, current challenges and future opportunities for regulating the TMME with nanomedicines will be provided.

Navoximod modulates local HSV-1 replication to reshape tumor immune microenvironment for enhanced immunotherapy via an injectable hydrogel.

Oncolytic virotherapy can lead to tumor lysis and systemic anti-tumor immunity, but the therapeutic potential in humans is limited due to the impaired virus replication and the insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). To solve the above problems, we identified that Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor Navoximod promoted herpes simplex virus type 1 (HSV-1) replication and HSV-1-mediated oncolysis in tumor cells, making it a promising combination modality with HSV-1-based virotherapy. Thus, we loaded HSV-1 and Navoximod together in an injectable and biocompatible hydrogel (V-Navo@gel) for hepatocellular carcinoma (HCC) virotherapy. The hydrogel formed a local delivery reservoir to maximize the viral replication and distribution at the tumor site with a single-dose injection. Notably, V-Navo@gel improved the disease-free survival time of HCC- bearing mice and protects the mice against tumor recurrence. What's more, V-Navo@gel also showed an effective therapeutic efficacy in the rabbit orthotopic liver cancer model. Mechanistically, we further discovered that our combination strategy entirely reprogramed the TME through single-cell RNA sequencing. All these results collectively indicated that the combination of Navoximod with HSV-1 could boost the viral replication and reshape TME for tumor eradication through the hydrogel reservoir.

Remodeling Tumor-Associated Neutrophils to Enhance Dendritic Cell-Based HCC Neoantigen Nano-Vaccine Efficiency.

Hepatocellular carcinoma (HCC) commonly emerges in an immunologically "cold" state, thereafter protects it away from cytolytic attack by tumor-infiltrating lymphocytes, resulting in poor response to immunotherapy. Herein, an acidic/photo-sensitive dendritic cell (DCs)-based neoantigen nano-vaccine has been explored to convert tumor immune "cold" state into "hot", and remodel tumor-associated neutrophils to potentiate anticancer immune response for enhancing immunotherapy efficiency. The nano-vaccine is constructed by SiPCCl2 -hybridized mesoporous silica with coordination of Fe(III)-captopril, and coating with exfoliated membrane of matured DCs by H22-specific neoantigen stimulation. The nano-vaccines actively target H22 tumors and induce immunological cell death to boost tumor-associated antigen release by the generation of excess 1 O2 through photodynamic therapy, which act as in situ tumor vaccination to strengthen antitumor T-cell response against primary H22 tumor growth. Interestingly, the nano-vaccines are also home to lymph nodes to directly induce the activation and proliferation of neoantigen-specific T cells to suppress the primary/distal tumor growth. Moreover, the acidic-triggered captopril release in tumor microenvironment can polarize the protumoral N2 phenotype neutrophils to antitumor N1 phenotype for improving the immune effects to achieve complete tumor regression (83%) in H22-bearing mice and prolong the survival time. This work provides an alternative approach for developing novel HCC immunotherapy strategies.

Engineered Red Blood Cell Biomimetic Nanovesicle with Oxygen Self-Supply for Near-Infrared-II Fluorescence-Guided Synergetic Chemo-Photodynamic Therapy against Hypoxic Tumors.

The low bioavailability of photosensitizers (PSs) and the hypoxia nature of tumors often limit the efficacy of current photodynamic therapy (PDT). Therefore, improving the utilization of three essential components (PS, light, and O2) in tumors will enhance PDT efficacy substantially. Herein, we have developed a red blood cell (RBC) biomimetic theranostic nanovesicle (named SPN-Hb@RBCM) with improved photostability, accumulation of PSs, and oxygen self-supply ability to enhance PDT efficacy upon near-infrared (NIR) laser irradiation. Such a biomimetic nanovesicle was prepared by a red blood cell membrane (RBCM)-camouflaged hemoglobin (Hb)-linked semiconducting polymer nanoparticle (SPN-Hb). The RBCM coating enables the long-term circulation of SPN-Hb due to the membrane-mediated immune evasion, allowing for more effective PS accumulation in tumors. Under 808 nm laser irradiation, the photostable SPN can serve as both a photodynamic and a second-near-infrared-window (NIR-II) fluorescence imaging agent; meanwhile, the conjugated Hb can be used as an oxygen carrier to relieve tumor hypoxia for enhancing PDT efficacy. In addition, Hb can also react with the tumor microenvironment overproduced H2O2 to generate cytotoxic hydroxyl radicals (•OHs) for chemodynamic therapy (CDT), which further achieve synergistic effects for PDT. Thus, this study proposed a promising biomimetic theranostic nanoagent for enhancing tumor oxygenation and NIR-II fluorescence-guided synergetic CDT/PDT against hypoxic tumors.