A Domino‐Synthesized Dicoordinate Copper(I) Bis‐imidazopyridine Complex Triggering Cuproptosis/Ferroptosis for Enhanced Cancer Immunotherapy

Abstract

ABSTRACT Novel synthetic methods offer significant potential to accelerate drug development, yet there remains a largely unexplored area for efficiently synthesizing metal‐based anticancer agents. Herein, we report a novel solvothermal domino reaction of pyridine‐2‐methylamine (and its 4‐OCH 3 ‐substituted derivative), benzaldehyde, and CuCl 2 ∙2H 2 O, which simultaneously achieves ligand synthesis and coordination assembly in one pot and facilely affords innovative dinuclear dicoordinate copper(I) complexes ( Cu1 and Cu2 ) with the in situ‐formed bulky steric‐hindering tetraarylethane ligands featuring the bis‐imidazo[1,5‐ a ]pyridine scaffold. The unique geometry of Cu1 and Cu2 confers physiological stability and vacant coordination sites for efficiently catalyzing Fenton‐like reactions. Further studies reveal that Cu2 effectively elevates intracellular copper ion levels to induce cuproptosis, concurrently disrupting cellular redox homeostasis to trigger ferroptosis. The concurrent cuproptosis‐ferroptosis activation finally elicits significantly enhanced immunogenic cell death (ICD), which facilitates the antitumor activity of Cu2 . Moreover, in combination with immune checkpoint inhibitor α PD‐1, Cu2 exhibits improved immunotherapy effects. This work introduces the first small‐molecule copper complex that achieves immunotherapy potentiation through cuproptosis‐ferroptosis‐ICD induction and provides a new pathway for accessing innovative metal‐based antitumor agents through such a rationally designed domino reaction.