Three‐Pronged Induction of Tumor Calcification Synergistic Calcium Immunotherapy Enables Diagnosis and Cure of Cancer

Abstract Tumor calcification is considered to have the superiority of integrating tumor diagnosis and treatment, and it also has been found to be a predictor of favorable prognosis. However, selecting suitable nanocarriers and therapeutic drugs to maximize the tumor calcification efficiency are key factors for improving calcification‐medicated theranostics. This study performs a multi‐channel calcification nanoinitiator (CalNI, i.e., BP‐Cur‐Ca@P KLAK ) by loading curcumin (Cur) and depositing Ca 2+ on black phosphorus (BP) and combined carrying mitochondria‐targeting cytotoxic peptide KLAK to boost a triple‐induced tumor calcification. CalNI preferentially accumulates inside tumor mitochondria and induces multilevel calcification promotion by the three combined effects of (i) the degradation of BP into PO 4 3− provides the phosphorus source required for calcification; (ii) burst of calcium ions can directly induce cellular calcium overload; (iii) Cur can inhibit calcium efflux thus further aggravate intracellular calcium stress. Moreover, KLAK exhibited enhanced mitochondrial synergistic toxic effects. Notably, the potential function of CalNI on the regulation of macrophage polarization could completely reverse the immunosuppressive microenvironment, and activate the initiation of T cell‐mediated immune response. Therefore, this three‐pronged CalNI showed a huge promise to be an alternative to conventional oncology therapy, which presents a more satisfactory therapeutic efficiency than any kind of single induction mode.