Abstract

Cancer immunotherapy harnesses the immune system to combat cancer, yet tumors often evade immune surveillance through immunosuppressive cells. Herein, we report an organic semiconducting sono-metallo-detonated immunobomb (SMIB) to spatiotemporally tame immunosuppressive cells in situ. SMIB consists of an amphiphilic semiconducting polymer (SP) with a repeatable thiophene-based Schiff base serving as an iron ion chelator (Fe3+). SMIB increases sonochemical activity through iron chelation and reduces immunosuppressive cell differentiation with metals and sonochemicals, thereby decreasing the irradiation dose. Upon ultrasound irradiation, SMIB acts as a sono-metallo-detonated immunobomb and inhibits Tregs via the mTOR pathway and M2 macrophage polarization through GPX4 regulation. Ultrasensitized sono-generated reactive oxygen species also promote activation of antigen-presenting cells in deep solid tumors (1 cm), resulting in cytotoxic T cell infiltration and enhanced antitumor efficacy. This platform provides a versatile approach for synergistic sono- and metalloregulation of immunosuppressive cells in situ.