Roles of the cGAS-STING signaling pathway in viral latency

Viral latency is a sophisticated survival strategy that allows the viral genome to persist indefinitely while remaining invisible to immune surveillance. This stealth impedes eradication, and episodic reactivation compounds the hurdle, necessitating therapeutic innovation. Recently, increasing evidence has indicated that the cGAS-STING pathway, which senses nonself or damaged DNA, plays vital roles in the establishment, maintenance, and reversal of latency in a subset of viruses. Given its central role in triggering innate immune responses, the cGAS-STING pathway has emerged as a high-priority target for therapeutic intervention. Here, we outline the multilayered arms race between latent viruses and the cGAS-STING pathway. Latent viruses generally conceal their genomes from cGAS, disrupt cGAS-STING signaling to limit innate immune responses, and subsequently deploy latency-associated factors to maintain pathway silencing and evade immune surveillance. We also elucidated the paradoxical engagement of cGAS-STING during reactivation. Motivated by encouraging preclinical data on STING agonists and the central role of the STING signaling pathway in cell fate decisions, we synthesized the current knowledge and proposed targeting this pathway for therapeutic intervention to reduce viral latency.