The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential.

Abstract

The cGAS/STING pathway is a central innate immune DNA-sensing system that links aberrant DNA species to innate immune and stress-response transcriptional programs and has emerged as a key regulator of tumor-immune interactions. In cancer, pathway outputs are shaped by interconnected downstream signaling modules, including type I IFN, NF-κB, autophagy, and stress-metabolic checkpoints, as well as by stringent spatial and biochemical regulation of both cGAS and STING. When activation is acute and appropriately compartmentalized, cGAS/STING signaling promotes antitumor immunity across multiple cellular compartments in the tumor microenvironment, supporting DC cross-priming and cytotoxic lymphocyte responses. In contrast, chronic or dysregulated activation rewires downstream signaling toward stress-adaptive and inflammatory programs that promote tumor progression, metastasis, and immune dysfunction, including deleterious effects in lymphocytes and the induction of suppressive myeloid and B cell populations. Here, we examine how context determines the consequences of cGAS/STING activation in cancer, review emerging therapeutic strategies that modulate this pathway, and discuss how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation.