Stimuli‐Responsive Heterobimetallic Prodrug Platform Enables In Situ Copper Complex Synthesis and Photosensitizer Activation for Targeted Chemo‐Photodynamic‐Immunotherapy

ABSTRACT Enhancing therapeutic efficacy while reducing toxicity is a central objective of cancer treatment, and the precise, synchronous activation of combination therapies represents an effective strategy to address this issue. Herein, we design a heterobimetallic prodrug ( LM‐RCu ) platform that enables in situ synthesis of cytotoxic copper (Cu) complex with concurrent activation of metal‐based photosensitizer via intramolecular transmetalation to achieve tumor‐targeted chemo‐photodynamic‐immunotherapy. The general LM‐RCu contains a stimuli‐responsive diethyldithiocarbamate ( DTC ) prochelator, a quenched Ru/Ir/Os‐based photosensitizer (“OFF” state), and a DPA‐Cu moiety, which skillfully acts as both Cu 2+ reservoir for DTC and quencher for photosensitizers. Upon tumor‐specific stimulation, structurally tunable LM‐RCu releases DTC, which chelates Cu 2+ from intramolecular DPA‐Cu to in situ synthesize cytotoxic Cu(DTC) 2 complex, while dissociation of DPA‐Cu simultaneously activates photosensitizer (“ON” state). Representatively, the heterobimetallic Ru‐Cu prodrug bRu‐BCu is selectively triggered by tumor‐elevated ROS to generate Cu(DTC) 2 and synchronously activate Ru‐based photosensitizer. Upon light irradiation, the activated photosensitizer produces type I/II ROS for cells killing while promoting more DTC release, thereby driving the self‐boosting loop of Cu(DTC) 2 generation and photosensitizer activation, inducing immunogenic PANoptosis to stimulate potent immune responses against primary/distant tumors with minimal toxicity. Overall, this universal and versatile prodrug platform provides an innovative strategy for precise and effective cancer therapy.