A Coordination Engineered Intramolecular Junction Polymer Unlocks IDO1 Inhibition and Cuproptosis to Enable Potent Immunotherapy

ABSTRACT Owing to poor lymphocyte infiltration, abundant immunosuppressive cells, and abnormal metabolism, the immunosuppressive tumor microenvironment (ITME) remains a primary challenge for effective cancer immunotherapy. A coordination engineering strategy was employed in this study to design an intramolecular junction polymer CuBr‐ dptz ‐CuCl‐ dptz ( dptz = 3,6‐di(pyridin‐4‐yl)‐1,2,4,5‐tetrazine), unlocking three synergistic antitumor cascades, IDO1 biobromination, cuproptosis, and apoptosis, within an integrated single material platform. The pyridinic nitrogen atoms of dptz coordinate to Cu(I) centers bridged by alternating Cu–Br and Cu─Cl chains. The intramolecular junction optimizes charge separation and d‐band centers, and together with electron‐withdrawing dptz stabilizes a high Cu + fraction (∼80.33%). Density functional theory calculations identified low‐energy pathways for hydrogen peroxide dissociation to hydroxyl radical and its conversion to oxygen, accounting for the high catalytic efficiency. Released Cu + potentiates cuproptosis by boosting cellular tricarboxylic acid cycle dependence and triggering dihydrolipoamide S‐acetyltransferase oligomerization and proteotoxic stress. Meanwhile, liberated Br − converts enzymatically to HBrO to realize functional IDO1 biobromination. Combined with apoptosis, the three‐pathway cascade synergy enhances lymphocyte infiltration, promotes anti‐tumor M1 macrophage polarization, and remodels ITME metabolism, ultimately activating robust systemic antitumor immunity. This work establishes intramolecular junction coordination polymers as a versatile single‐platform paradigm for multi‐mechanism synergistic cancer immunotherapy.