Near-Infrared-II-Activated Transition Metal(II)-Coordinated Ligand Radical Primes Robust Anticancer Immunity

Photoactivatable metallodrugs combining tumor cell eradication and immune stimulation hold immense promise for targeted cancer therapy. However, limitations such as oxygen dependence, narrow visible light responsiveness, and poor immunogenicity hinder their efficacy in deep solid tumors with hypoxic and immunosuppressive microenvironments. Herein, we present a novel design strategy for transition metal(II)-coordinated ligand radicals exhibiting intense near-infrared-II (NIR-II) absorption, unique endoplasmic reticulum-targeting capability, and oxygen-independent photothermal performance, effectively addressing these constraints. Proof-of-concept results demonstrate the potent efficacy of our cobalt(II)-coordinated ligand radical (<b>BPDP-Co</b>) in inducing highly immunogenic pyroptosis in tumor cells under both normoxic and severe hypoxic conditions upon 1064 nm laser irradiation. This NIR-II activation triggers the release of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, fueling a robust antitumor immune response. <i>In vivo</i> studies demonstrate that treatment with <b>BPDP-Co</b>/NIR-II significantly inhibited 4T1 tumor growth in BALB/c mice with a high inhibitory rate of 85.7%, highlighting its therapeutic potential in tumor immunotherapy.