Ir(III) Complexes Convert Cold to Hot Tumors via Ferroptosis/Necroptosis-Driven Immunogenic Cell Death and Photosensitized CD47 Downregulation

Photosensitizers engineered for spatiotemporal modulation of cluster of differentiation 47 (CD47) in hypoxic tumor microenvironments (TMEs) disrupt immunosuppressive circuits. Herein, we develop two Ir(III) complexes ( Ir1 and Ir2 ) that function as photodynamic therapy (PDT) agents via Type-I/II mechanisms, overcoming hypoxic constraints. Under 630 nm irradiation, Ir1 -mediated PDT ROS-dependently downregulates CD47, enabling spatial control that circumvents hematotoxicity. Concurrently, Ir1 -mediated PDT triggers immunogenic cell death (ICD) via ferroptosis-necroptosis synergy and blocks the CD47-SIRPα immune checkpoint, while promoting M1-polarization of tumor-associated macrophages. In 4T1 murine breast cancer models, Ir1 -PDT achieves potent tumor suppression and transforms immunologically “cold” tumors into “hot” lesions through the synergistic interplay of ICD and CD47 pathway disruption. Collectively, this work establishes a photodynamic CD47-signaling platform for precise immune modulation, offering a clinically translatable alternative to conventional CD47-targeting therapies.