An Insight into the cGAS–STING Pathway Modulation by Metal Complexes to Initiate Immunogenic Cell Death in Cancer

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of antitumor immunity, capable of converting immunologically "cold" tumors into inflamed, immune-responsive states. Cyclic dinucleotide (CDN) agonists have clinically validated the impact of targeting this axis but are limited by poor pharmacokinetics, limited tumor penetration, and delivery challenges. Non-CDN based small-molecule modulators such as MSA-2 and amidobenzimidazole (ABZI) directly modulate cGAS-STING signaling. Beyond direct receptor agonism, coupling with metals offer platforms with complementary strategies to engage and amplify cGAS-STING signaling. Complexes incorporating platinum, ruthenium, iridium, rhodium, gold, copper, manganese, or zinc exploit redox activity, coordination versatility, and photophysical properties to induce nuclear or mitochondrial DNA stress, disrupt organelle homeostasis, and promote immunogenic cell death. By coupling STING activation to ferroptosis, pyroptosis, or cuproptosis, these complexes form the foundation of self-emerging design principles with elaborate mechanistic insights, and translational challenges shaping immune modulation for therapeutics.