Boosting antitumor immunity via a tumor microenvironment-responsive transformable trifecta nanovaccine

Abstract

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 should 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) were liberated in situ after immunogenic cell death induced by TriNV-based photoimmunotherapy. Under TME, soft-transformed TriNV improved the uptake of TAAs by DCs to enhance acquired immunity. Second, the self-adjuvating TriNV and the TME-responsive released Mn2+ synergistically promoted DC maturation and macrophage M1 polarization by augmenting the stimulator of interferon genes (STING) activation to further amplify T-cell immune responses. Moreover, the decomposition of MnO2 within the core of TriNV exhausted glutathione (GSH) and facilitated O2 release to alleviate hypoxia in TME, thereby overcoming the chemical obstacles of the TME to further mitigate immunosuppression. Thus, the TriNV remarkably eradicated primary tumors and inhibited distant metastasis, demonstrating great potential as a feasible and effective ISTV nanoplatform for combating poorly immunogenic solid tumors.