Th9 cells at the intersection of IBD and colorectal cancer: a context-dependent factor in carcinogenesis

The differentiation of naïve T cells into the Th9 phenotype is driven by the synergistic effects of IL-4 and TGF-β, leading to the secretion of their hallmark cytokine, interleukin-9 (IL-9). Known for their critical roles in mucosal immunopathology, Th9 cells are particularly prominent in the gastrointestinal tract, where they contribute to autoimmunity, inflammation, and tissue damage. Recent studies have highlighted the paradoxical role of Th9 cells in colorectal carcinogenesis, revealing that their function is highly context-dependent. In the chronically inflamed microenvironment of inflammatory bowel disease (IBD), Th9 cells exhibit pro-tumorigenic functions. Th9 cells drive the transition to colitis-associated cancer (CAC) by impairing intestinal barrier integrity and promoting epithelial cell survival through PU.1/IL-6/STAT3 signaling and direct oncogene upregulation. Conversely, in sporadic colorectal cancer (CRC), Th9-derived IL-9 exerts anti-tumorigenic effects by enhancing immune surveillance, specifically through the recruitment and activation of mast cells and CD8 + cytotoxic T lymphocytes. Given the complex and often contradictory reports in the literature, this review provides an in-depth analysis of the distinct molecular mechanisms by which Th9 cells shape the tumor microenvironment. By explicitly distinguishing between inflammation-driven carcinogenesis (CAC) and sporadic CRC, this article aims to reconcile current literature and discover emerging therapeutic strategies, such as targeted metabolic reprogramming, to selectively suppress pathogenic Th9 cells without compromising systemic anti-tumor immunity.