Supramolecular Metallacycle Enables Esterase-Responsive and Endoplasmic Reticulum-Associated Pathway Activation for Synergistic Photothermal Immunotherapy

Supramolecular metallacycles present a unique platform for integrating therapeutic modalities; yet, their application for activating the cGAS-STING pathway remains to be explored. Herein, we report an endoplasmic reticulum (ER)-accumulated supramolecular Pt(II) metallacycle (<b>M2</b>) that enables esterase-responsive cGAS-STING activation for synergistic photothermal immunotherapy. This nanoplatform is engineered to codeliver an NIR aza-BODIPY photothermal agent, a chemotherapeutic Pt(II) unit, and the STING agonist DMXAA. Upon DSPE-PEG encapsulation, <b>M2</b> nanoparticles (NPs) selectively accumulate in tumor ER via caveolin-mediated endocytosis. Upon delivery to the tumor ER, intracellular esterase-triggered NPs disassembly, amplified by photothermal stimulation, releases DMXAA to directly activate STING. Concurrently, photothermal/chemotherapy synergy induces immunogenic cell death, releasing damage-associated molecular patterns while generating cytosolic dsDNA to amplify cGAS-STING signaling. This dual-pathway activation evokes potent antitumor immunity, achieving primary tumor ablation and suppression of distant metastases in mouse models. This work presents the potential of supramolecular coordination complexes for integrating photothermal therapy with immune-related functions in cancer treatment.