Conventional light-driven cancer therapeutics require oxygen and visible light to indirectly damage biomolecules, limiting their efficacy in deep, hypoxic tumours. Here we report the use of near-infrared-activated small-molecule Pt(IV) photooxidants to directly oxidize intracellular biomolecules in an oxygen-independent manner, achieving controllable and effective elimination of cancer stem cells. These Pt(IV) complexes accumulate in the endoplasmic reticulum and show low toxicity in the dark. Upon irradiation, the resultant metal-enhanced photooxidation effect causes them to robustly photooxidize survival-related biomolecules, induce intense oxidative stress, disrupt intracellular pH (pHi) homeostasis and initiate nonclassical necrosis. In vivo experiments confirm that the lead photooxidant can effectively inhibit tumour growth, suppress metastasis and activate the immune system. Our study validates the concept of metal-enhanced photooxidation and the subsequent chemotherapeutic applications, supporting the development of such localized photooxidants to directly damage intracellular biomolecules and decrease pHi as a strategy for effective metal-based drugs.
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