Design Of Novel Immunogenic Cell Death Nanomedicines For Activation Of Innate Immunity And Enhanced Cancer Immunotherapy

In recent years,immunogenic cell death(ICD)therapy has demonstrated irreplaceable prospects compared to traditional therapies in the forefront of cancer treatment research,due to its ability to activate innate and adaptive anti-tumor immunity,leading to stronger tumor elimination capacity and smaller side effects.With the clarification of the mechanism of ICD and its intrinsic correlation with anti-tumor immunity,it has been cosidered to enhance cancer cell antigen exposure and inducing antigen presentation cell antigen loading and activation as both the theoretical basis for the generation and maintenance of antigen-specific T cell responses by ICD therapy,as well as the design criterion for ICD inducing drugs.Existing ICD inducers are primarily identified from the pharmacological effects discovery of other clinical anti-tumor drugs,most of which could not directly target and induce stress in endoplasmic reticulum therfore lead so weak immunogenity that masked by reprogrammed tumor metabolism and immune microenvironment,preventing the exposure of tumor antigens and resulting in immune tolerance.Thus,to enhance the immunogenic cytotoxicity of ICD induces and combine ICD therapy with multipul immunotherapies signs highly importance to enhanced anti-tumor immunity and immune memory,meanwhile the research emphasis of current ICD inducers’ development and application.Firstly,to address the issue of the limited induction efficacy of immunogenic photodynamic therapy by intracellular reactive oxygen species(ROS)accumulation,this research focuses on a strategy of sustained oxidative stress enhancement that disrupts metabolic balance homeostasis.By coordinating the ratio and sustained release ability of small molecular metabolic regulators,a nanodrug was developed with abilities of efficient and durable cell metabolic homeostasis sustained and intracellular oxidative stress enhancement,to achieve enhanced immunogenic cytotoxicity and establish anti-tumor immune memory in triple-negative breast cancer model with low mutation burden.Subsequently,given the resistance of the "cold" tumor immune environment to tumor infiltrating T cell and antigen-specific immune responses,this research aims to develope novel ICD therapy involving stimulator of interferon genes(STING)pathway to deal with the masked antigenicity of dying tumor cells by immunosuppressive microenvironment.Inspired by STING agonists-induced T cell toxicity,we have clearfied the mechenism how murine STING agonist DMXAA induces endoplasmic reticulum stress and immunogenic cell death through abnormal dimerization or polymerization of STING protein at extramly high doses,and then proposed "STING overload" therapy to coordinates the fusion of innate and adaptive immune processes through DMXAA monotherapy.This design has demonstrated strong anti-tumor immune efficacy in murine subcutaneous tumor models and post-operative residual lesion recurrence models,representing a prospective approach with simultaneously enhanced antigenic and adjuvant properties in anti-tumor immune recognition.Such STING agonists-deriven ICD driven will,on one hand,facilitate classic STING agonists-improved anti-tumor immune breakthrough peripheral tolerance,and on the other hand,strengthen the connection between immune recognition and killing,providing a fundamentally new perspective for the development of novel ICD inducers.Finally,to address the limitation of STING agonists therapy with narrow therapeutic window,non-specific systemic immune activation and negative regulation towards peripheral tolerance effected on the efficacy and safety of "STING overload" immunotherapy,this research conducts on microenvironment immune tolerance modulation and precise "STING overload" induction.Inspired by tumor cell membrane-induced homologous targeting and cell differential phagocytosis behavior,a homologous cell membrane-coated nanoparticle i SONA was developed with adjusted dose and preparation in order to effective tumor cellular targeting and anti-tumor adaptive immunity activation,while minimizing tolerance negative regulation and immune system side effects.The design of the new dosage form expands the effectiveness of SITNG overload therapy and seeks the optimal balance between toxicity and effectiveness,thereby opening up a therapeutic window for achieving efficient antitumor immunity.In the subcutaneous tumor and lung metastasis model of murine triple negative breast cancer,i SONA showed excellent immune microenvironment regulation ability and strong systemic anti-tumor immunity.In addition,i SONA also has the potential to directly stimulate dendritic cell activation as a vaccine adjuvant,relying on which differentiated tissue distribution ability and selective cell uptake behavior,therefore has advantages in accurately targeting tumor cells for ICD induction and alleviating STING agonist dose-dependent toxic side effects in peripheral immune organs and major organs.In summary,the innovative "STING overload" therapy is a novel ICD therapy that combines tumor cell killing and immune activation,which not only reveals the potential role of the STING pathway in tumor immunity but also provides a new application of ICD-guided anti-tumor immune therapy,opening up a new paradigm for tumor immunotherapy.