Colorectal most cancers (CRC) development is critically pushed by its hydrogen sulfide (H₂S)-rich tumor microenvironment, which paradoxically confers chemoresistance by stabilizing redox homeostasis whereas selling immune evasion. To remodel this vulnerability right into a therapeutic alternative, we developed an H₂S-responsive twin prodrug system (As-Cu/DSF@TPP⁺) that leverages endogenous H₂S overexpression as a biochemical set off. This method operates via a cascading mechanism: (1) Tumor-specific H₂S activation reduces unhazardous As⁵⁺ to cytotoxic As³ ⁺, disrupting mitochondrial copper homeostasis and initiating cuproptosis by way of lipoylated protein aggregation; (2) Launched Cu²⁺ reacts with H₂S to generate photothermally energetic copper sulfide, enabling localized hyperthermia remedy; (3) Disulfiram-derived CuET establishes a self-amplifying loop, concurrently depleting H₂S via CBS enzyme inhibition and amplifying copper accumulation. The coordinated motion achieves twin therapeutic breakthroughs: cascading cuproptosis via mitochondrial copper overload and Fe-S cluster destabilization, coupled with immunogenic cell death-driven TME transforming that enhances dendritic cell maturation and cytotoxic T-cell infiltration. By integrating H₂S scavenging, cuproptosis induction, and photothermal-immunotherapy, this technique establishes a “gasoline signaling molecule-programmed nanotherapy” paradigm. It not solely overcomes CRC-specific resistance mechanisms but in addition gives a common framework for concentrating on H₂S-high malignancies, demonstrating how endogenous tumor protection techniques will be repurposed into precision therapeutic weapons.
