The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential
Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng
Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng
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Review Series

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.

Authors

Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng

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Figure 3

Therapeutic targeting of cGAS-STING for cancer treatment.

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Therapeutic targeting of cGAS-STING for cancer treatment. Multiple strat...
Multiple strategies aim to harness cGAS/STING signaling for antitumor immunity, each engaging a distinct node of the pathway. (i) Direct STING agonists, including CDNs, non-CDN small molecules, and tumor-targeted ADCs engage STING directly to induce IRF3- and NF-κB–driven transcription. (ii) Extracellular cGAMP hydrolase inhibitors blocking ENPP1 prevent degradation of tumor-derived cGAMP in the extracellular space, sustaining paracrine STING activation. (iii) DDR inhibitors and radiation (PARPi, ATRi, CHK1i, ionizing radiation) generate cytosolic DNA and micronuclei that activate tumor-intrinsic cGAS, supplying endogenous cGAMP to license host STING. (iv) Viral platforms such as T-VEC and other oncolytic viruses provide foreign DNA that activates cGAS in infected and bystander cells. Convergent activation of the cGAS-STING-IRF3/NF-κB axis induces IFN-I and ISGs expression. The clinical utility of these strategies depends on tuning the magnitude, duration, and cellular compartmentalization of activation to achieve durable immune engagement while limiting chronic inflammation and species-specific differences in human STING responsiveness.