A Small-Molecule Platform Demonstrates Light-Activated Synergy Between Cuproptosis and Photodynamic Tumor Therapy

Cuproptosis offers a strategy to overcome chemotherapy resistance; however, it lacks tumor selectivity. Although glutathione (GSH) is highly expressed in tumors and serves as a conventional trigger for selective cuproptosis, it paradoxically inhibits cuproptosis by binding copper ions. Although recent nanoplatforms combined photodynamic therapy (PDT) and cuproptosis to address these challenges, their complexity raises safety concerns and obscures mechanisms. Herein, a copper(II) complex (NC), synthesized by linking 8-hydroxyquinoline to Nile Blue, represents the first small-molecule platform to synergize PDT and cuproptosis. Upon near-infrared irradiation, NC generates superoxide anions (O₂^•-), reducing GSH copper-binding capacity, thereby liberating copper ions and selectively inducing cuproptosis. In murine tumor models, NC demonstrated high biosafety and superior tumor suppression to PDT alone, achieving complete inhibition over 14 d. Thus, NC establishes PDT as a controllable cuproptosis inducer, converting GSH from inhibitor to trigger and expanding the therapeutic potential of both modalities.