Personalized Biomineralized Tumor Whole-Component Vaccine for Synergistic cGAS-STING/aTIGIT Immunotherapy

Conventional adjuvants such as aluminum salts rarely drive robust Th1 immunity, which limits cancer vaccine efficacy. A double-stranded DNA-loaded manganese phosphate nanoadjuvant was generated by dsDNA-templated biomimetic mineralization. The resulting DNA@MnP exhibited favorable physiological stability and pH-responsive release properties: at pH 5.5, the cumulative release rates of Mn2+ and DNA reached 72% and 78%, respectively, within 12 h. Following cytosolic delivery, released Mn2+ from DNA@MnP could augment the cGAS recognition of dsDNA. The cooperative action of Mn2+ and dsDNA produced cascade amplification that potently activated the cGAS-STING pathway in dendritic cells. In vitro experiments demonstrated that DNA@MnP significantly promoted the maturation of BMDCs (with a maturation rate 2.10-fold elevation compared with the control group) and induced RAW264.7 macrophages to polarize toward the M1 phenotype (with an M1/M2 ratio 8.31-fold elevation compared with the control group). Animal experiments demonstrated that DNA@MnP not only significantly enhanced antigen-specific humoral immunity, achieving a 16-fold increase in IgG titers, and elicited a balanced Th1/Th2 response but also effectively activated both innate and adaptive antitumor immunity. Furthermore, this platform was extended to develop a personalized tumor vaccine by encapsulating tumor lysates (TLs) into TLs-loaded manganese phosphate nanovaccines (TLs@MnP). When coadministered with an anti-TIGIT antibody, it potently suppressed tumor growth, recurrence, and metastasis: in the postoperative recurrence model, 42.9% of mice in the TLs@MnP multidose combined with aTIGIT group achieved long-term tumor-free survival. Therefore, this study presented a manganese phosphate-based biomineralization strategy for the concise preparation of autologous tumor vaccines, opening a promising avenue for personalized immunotherapy and clinical translation.