Currently, patients receiving cancer treatments routinely suffer from distressing toxic effects, most originating from premature drug leakage, poor biocompatibility, and off-targeting. For tackling this challenge, we construct an intracellular Ca2+ cascade for tumor therapy via photothermal activation of TRPV1 channels. The nanoplatform creates an artificial calcium overloading stress in specific tumor cells, which is responsible for efficient cell death. Notably, this efficient treatment is activated by mild acidity and TRPV1 channels simultaneously, which contributes to precise tumor therapy and is not limited to hypoxic tumor. In addition, Ca2+ possesses inherent unique biological effect and normal cells are more tolerant of the undesirable destructive influence than tumor cells. The Ca2+ overload leads to cell death due to mitochondrial dysfunction (upregulation of Caspase-3, cytochrome c, and downregulation of Bcl-2 and ATP), and in vivo, the released photothermal CuS nanoparticles allow an enhanced 3D photoacoustic imaging and provide instant diagnosis.