Biomineralized Synthesis Of Autologous Cancer Vaccine With CGAS-STING Activating Capacity For Cancer Immunotherapy

Cancer vaccine serves as an immunotherapeutic modality effectively suppressing tumor growth by training the patients’ intrinsic immune systems to arouse systemic antitumor responses.Generally,cancer vaccines are composed of tumor antigens(e.g.,proteins,peptides,or nucleic acids)and adjuvants including both immune agonists and/or delivery carriers to collectively promote antigen retention,cellular uptake,and subsequent antigen cross presentation.The activation of cGAS-STING(cyclic GMPAMP Synthase-Stimulator of Interferon Gene)pathway with suitable agonists has emerged as a promising strategy for improved cancer treatment due to its high capacity in eliciting type-I interferon secretion and priming CD8+T cells activation.However,the currently available cGAS-STING agonists are still challenged by intricate synthesis,rapid degradation,and low cellular uptake efficacy.Therefore,by utilizing the high capacity of micro/nano delivery system in enabling efficient encapsulation,controlled release and transmembrane delivery of different molecules/ions,this master’s thesis presents two novel biomineralization approaches for the synthesis of tumor vaccines with cGASSTING activating capacity.The detailed mechanisms underlying their high efficacies in inducing adaptive antitumor responses and preventing the postoperative tumor relapse are also studied.The detailed research content is summarized as follows:1.Biomineralization-inspired synthesis of DNA@CaCO3 particles and study of its immunological effects.In this section,inspired by the capacity of double-stranded deoxyribonucleic acid(dsDNA)in activating cGAS-STING pathway,dsDNA moelcules of various sources are utilized as the template to mediate the biomineralization synthesis of calcium carbonate particles.The yielded rod-shape DNA@CaCO3 particles with excellent stability and biocompatibility are able to promote the cellular uptake and endosome/lysosome escape of dsDNA and thus activate the cGAS-STING pathway.Upon intratumoral injection,it could effectively inhibit tumor growth by concurrently stimulating both innate and adaptive antitumor immune responses to reverse the tumor immunosuppression,therefore significantly inhibiting the tumor growth.2.Biomineralized synthesis of personalized autologous cancer vaccine with intrinsic cGAS-STING activating capacity for postoperative tumor recurrence inhibition.In this study,whole tumor cell lysate(TCL)with both protein antigens and dsDNA are employed as template to induce mineralization of CaCO3.The as-prepared TCL@CaCO3 could effectively activate cGAS-STING pathway,promote dendritic cell maturation and subsequent antigen cross-presentation to prime antigen-specific CD8+ T cell expansion.As a result,autologous TCL@CaCO3 vaccine prepared from the TCLs of resected tumors is then found to be capable of eliciting robust antitumor immune responses to reject the growth of residual tumors in an incompletedly resected B16 melanoma model,particularly when combined with immune checkpoint blockade(ICB)therapy.3.Biomineralization-inspired synthesis manganese-based cGAS-STING stimulating cancer vaccine for postsurgical immunotherapy.Herein,we develop a protein/polysaccharide mediated biomineralization synthesis of manganese phosphate(MnP)nanoflower.The as-prepared MnP based tumor vaccines with high stability and cGAS-STING activating capacity are able to concurrently stimulating the antigenspecific CD8+ T cells,IgA and IgG immunological responses.As a result,the TCLderived autologous TCL@MnP vaccine can significantly inhibit tumor replase when in combination with anti-PD-1 immunotherapy.In summary,this thesis develops two biomineralization approaches for preparation of cGAS-STING activating cancer vaccines,and elucites their detailed mechanisms in eliciting both innate and adaptive antitumor immune responses,as well as their capacities in inhibiting tumor recurrence when synergized with anti-PD-1 immunotherapy.The construction of cGAS-STING activating autologous cancer vaccines paves an avenue for safe and effective strategy to suppress postoperative tumor replase.