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In situ tumor vaccines (ISTVs) hold great potential in tumor immunotherapy, however, three major obstacles, including inadequate endogenous antigen uptake by dendritic cells (DCs), weak T‐cell immune responses, and stubborn immunosuppressive tumor microenvironment (TME), still need to be fully addressed. Herein, a trifecta nanovaccine (TriNV) with TME‐responsive transformable ability is developed to tri‐boost antitumor immunity. First, sufficient endogenous tumor‐associated antigens (TAAs) are liberated in situ after immunogenic cell death is induced via TriNV‐based photoimmunotherapy. In the TME, soft‐transformed TriNV improves the uptake of TAAs by DCs to enhance acquired immunity. Second, the self‐adjuvating TriNV and the TME‐responsive released Mn2+ synergistically promote DC maturation and macrophage M1 polarization by augmenting the stimulator of interferon genes activation to further amplify T‐cell immune responses. Moreover, the decomposition of MnO2 within the core of TriNV exhausts glutathione and facilitates O2 release to alleviate hypoxia in the TME, thereby overcoming the chemical obstacles of the TME to further mitigate immunosuppression. Thus, TriNV remarkably eradicates primary tumors and inhibits distant metastasis, thus demonstrating great potential as a feasible and effective ISTV nanoplatform for combating poorly immunogenic solid tumors. [ABSTRACT FROM AUTHOR]