γδ T cells: Dual function in modulating inflammation-cancer transition in colorectal carcinogenesis

Chronic intestinal inflammation is a significant risk factor for colorectal cancer (CRC), and gamma-delta (γδ) T cells have emerged as pivotal regulators in this transition. γδ T cells are now understood to play a dual role in inflammatory bowel disease (IBD), contributing to both anti-inflammatory and pro-inflammatory responses. They facilitate mucosal healing and maintain epithelial barrier integrity by secreting factors such as interleukin-22 (IL-22). Conversely, they can intensify chronic intestinal inflammation by releasing cytokines like IL-17. Interestingly, the dual functionality of γδ T cells has been documented in CRC. Certain subsets of γδ T cells contribute to anti-tumor immunity by exerting cytotoxic effects and producing interferon-γ (IFN-γ). In contrast, other subsets promote tumor progression by inducing immunosuppression and angiogenesis, primarily through the secretion of IL-17 and IL-22. Furthermore, the IL-17/IL-22-signal transducer and activator of transcription 3 (STAT3) signaling pathway has been identified as a critical mediator linking chronic intestinal inflammation to malignancy. This axis initially facilitates tissue repair; however, its prolonged activation can lead to oncogenic transformation of epithelial cells. Therefore, a comprehensive understanding of the dual roles of γδ T cells not only provides critical insights into the immunopathological mechanisms of CRC but also offers a theoretical basis for developing targeted immunotherapies. We summarized the preclinical and clinical progress of γδ T cells combined immunotherapy strategies. Preliminary clinical trials leveraging this knowledge have shown promising results in reducing inflammation and improving therapeutic outcomes, underscoring the translational potential of γδ T cell modulation in CRC treatment.