An integrated therapeutic strategy to enhance cuproptosis through adaptive activation and microenvironment remodeling of prodrug complexes

Abstract

Colorectal cancer (CRC) progression is critically driven by its hydrogen sulfide (H₂S)-rich tumor microenvironment, which paradoxically confers chemoresistance by stabilizing redox homeostasis while promoting immune evasion. To transform this vulnerability into a therapeutic opportunity, we developed an H₂S-responsive dual prodrug system (As-Cu/DSF@TPP⁺) that leverages endogenous H₂S overexpression as a biochemical trigger. This system operates through a cascading mechanism: (1) Tumor-specific H₂S activation reduces nontoxic As⁵⁺ to cytotoxic As³ ⁺, disrupting mitochondrial copper homeostasis and initiating cuproptosis via lipoylated protein aggregation; (2) Released Cu²⁺ reacts with H₂S to generate photothermally active copper sulfide, enabling localized hyperthermia therapy; (3) Disulfiram-derived CuET establishes a self-amplifying loop, simultaneously depleting H₂S through CBS enzyme inhibition and amplifying copper accumulation. The coordinated action achieves dual therapeutic breakthroughs: cascading cuproptosis through mitochondrial copper overload and Fe-S cluster destabilization, coupled with immunogenic cell death-driven TME remodeling that enhances dendritic cell maturation and cytotoxic T-cell infiltration. By integrating H₂S scavenging, cuproptosis induction, and photothermal-immunotherapy, this strategy establishes a "gas signaling molecule-programmed nanotherapy" paradigm. It not only overcomes CRC-specific resistance mechanisms but also provides a universal framework for targeting H₂S-high malignancies, demonstrating how endogenous tumor defense systems can be repurposed into precision therapeutic weapons.