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.