Inflammatory Bowel Disease (IBD)-Associated Colorectal Cancer (CRC): Is cGAS-STING Pathway Targeting the Key to Chemoprevention?

Abstract

Inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) remains a significant clinical challenge due to its link with chronic inflammation and the inherent limitations of current prevention and surveillance strategies. The cGAS-STING pathway has emerged as a key player in the immune regulation of inflammation-driven carcinogenesis, demonstrating both protective and pathogenic roles. This review examines the contrasting roles of the cGAS-STING signaling pathway in intestinal inflammation and colitis-associated cancer (CAC), emphasizing its promise as a target for cancer prevention strategies. Evidence suggests that modulating this pathway could preserve epithelial integrity, limit chronic inflammation, and bolster anti-tumor immunity. Despite advancements in therapies like mesalazine and surveillance colonoscopy programs, gaps in efficacy remain, particularly for Crohn's disease and high-risk populations. Future research should focus on integrating cGAS-STING-targeted approaches with existing modalities to provide personalized and less invasive strategies for CAC prevention. By harnessing this pathway's therapeutic potential, a paradigm shift in managing IBD-associated CRC may be achieved, addressing the challenges of long-term disease surveillance and prevention.

Keywords: cGAS-STING pathway; chemoprevention; colitis-associated colorectal cancer (CAC); inflammatory bowel disease (IBD); innate immunity.

Figure 1

Illustrates the cGAS-STING pathway, a critical link between DNA sensing and immune signaling. When cGAS recognizes cytosolic double-stranded DNA, it triggers the production of cGAMP, a second messenger that subsequently activates the endoplasmic reticulum-resident protein STING. This activation triggers a cascade involving TBK1 and IRF3, leading to type-I IFN and pro-inflammatory cytokine production to maintain immune homeostasis. Created in BioRender. Papadakos, S. (2025) https://BioRender.com/n3mootb (accessed on 6 April 2025).

Figure 2

This illustrates the multifaceted impact of STING signaling on intestinal homeostasis, including permeability, microbiota balance, mucus layer integrity, stem cell function, and goblet cell populations. STING depletion disrupts epithelial tight junctions, increasing permeability and promoting dysbiosis. It disrupts the regeneration of intestinal stem cells and impairs goblet cell function, leading to compromised integrity of the mucus barrier. Therapeutic targeting of STING signaling has shown potential to restore these functions and mitigate intestinal inflammation. Created in BioRender. Papadakos, S. (2025) https://BioRender.com/ekw7eio (accessed on 18 May 2025).

Figure 3

Tumor-suppressive roles of cGAS and STING signaling in inflammation-driven colorectal cancer. Loss of cGAS impairs epithelial barrier integrity, promotes chronic inflammation, and increases tumor burden via STAT3 activation and immune suppression. STING deficiency enhances pro-inflammatory cytokines, reduces IL-18 and IL-22 regulation, and disrupts tissue repair, collectively driving CAC progression. Created in BioRender. Papadakos, S. (2025) https://BioRender.com/uty1xz9 (accessed on 14 May 2025).