STAT3 interference-driven nanomodulators reverse lipid metabolism-associated chemoresistance and potentiate metalloimmunotherapy in breast cancer

Summary Clinical evidence has suggested that persistent STAT3 activation and alteration in lipid metabolism correlate with pathological progression in patients with breast cancer, driving resistance to chemotherapy. Herein, we show that H₂S, an endogenous gas signaling molecule, sensitizes breast cancer to chemotherapy by suppressing STAT3 signaling-mediated lipid metabolism and improves tumor immunogenicity. Moreover, we further identify Ni²⁺ as immune agonist for potent metalloimmunotherapy. The construction of an activable nanoplatform enables the controllable delivery of metal ions and H₂S gas, which triggers pyroptosis and mobilizes multiple immune cells to elicit systemic anti-tumor immunity in combination with chemotherapy. Moreover, the synergy with αPD-1 inhibits the progression of both primary and metastatic tumors. Our work highlights the potential of bioactive gas transmitters and nutrient metal ions for reversing the dual dilemmas of chemoresistance and low immunogenicity in breast cancer and thus provides a nanosensitization strategy to synergize with multiple clinical treatment modalities.