Synthesis Of Nanoinducers For Tumor Immunotherapy Through Novel Cell Death Modes

Cancer is one of the major diseases that seriously threaten human life and health.Chemotherapy,radiotherapy and surgery,the widely used clinical treatments,still face problems such as side effects and drug resistance.Immunotherapy is considered as a promising tumor treatment modality by activating the immune system to kill tumor.However,most tumors have low immunogenicity and immunosuppressive microenvironment.Inducing immunogenic death（ICD）of tumor cells can ameliorate the above problems and greatly improve the effect of immunotherapy.Currently,most of ICD are induced by apoptosis,but the resistance of tumor cells to apoptosis limits the efficacy of apoptosis-induced ICD.Therefore,it is important to develop novel cell death modalities with high immunogenicity for cancer immunotherapy.Cuproptosis is a recently discovered programmed cell death（PCD）that can effectively circumvent the resistance of tumor cells to apoptosis.However,whether cuproptosis can induce ICD and how to improve the immunotherapeutic effect of cuproptosis are still unresolved problems.Pyroptosis,an inflammatory cell death modality,have shown to activate anti-tumor immunity by reshaping the tumor immune microenvironment.Using the unique physicochemical properties of nanomaterials,the rational design of nanoinducer will help the development of tumor immunotherapy.Herein,we proposes two strategies to induce ICD by nanoinducers for antitumor immunotherapy,which are the nanoinducers enable both cuproptosis and pyroptosis,as well as the nanoinducers enable enhanced cuproptosis.The contents of the thesis are summarized as follows:In the first chapter,a brief overview of tumor therapy is presented,and then the therapeutic strategies of nanomaterials in immunotherapy and the new PCD including cuproptosis and pyroptosis are summaried.In the second chapter,the nanoinducers MOF-199 nanoparticles,which induces both cuproptosis and pyroptosis,was constructed to achieve antitumor immunotherapy against colon cancer.The nanoinducers show dual-responsive behavior to the excessive glutathione（GSH）and sulfuretted hydrogen（H₂S）in CT26 cells,which can activate cuproptosis and pyroptosis effectively by the Cu⁺and Cu_2-xS generated in situ.The excellent antitumor immunotherapeutic effect was also demonstrated in vivo in CT26-bearing mice model.In the third chapter,a cuproptosis-enhanced nanoinducer（Mn O₂@MOF-199@GOx）was constructed for antitumor immunotherapy for breast cancer.Using the porous structure and loading ability of MOF-199,Mn O₂@MOF-199@GOx was successfully prepared by loading GOx and Mn O₂simultaneously.This nanoinducers not only show excellent GSH and glucose depletion ability,but also generate oxygen to effectively alleviate glucose-depletion-exacerbated tumor hypoxia.The enhanced cuproptosis was also demonstrated in 4T1-bearing mice model with good antitumor immunotherapeutic effect.In the fourth chapter,the content of this thesis is summarized and an outlook for future work is presented.In summary,we designed two types of nanoinducers for antitumor immunotherapy by inducing novel PCD to improving immunogenicity of tumor cells,which achieves good therapeutic effects in subcutaneous tumor models.These studies provide new directions for antitumor immunotherapy.