Functional heterogeneity of γδ T cells in colorectal cancer.

Colorectal cancer (CRC) remains a significant global health concern. Improving the efficacy of immunotherapy, particularly for microsatellite-stable tumors, requires a better understanding of the unconventional T-cell populations that regulate intestinal immunity. γδ T cells are uniquely positioned at the epithelial barrier and function as rapid sentinels, recognizing stress signals independently of classical antigen presentation. In a healthy colon, γδ intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) form separate compartments influenced by tissue-specific butyrophilin-like (BTNL) interactions, microbiota-derived signals, and cytokine environments. These signals imprint divergent effector programs, ranging from IFN-γ-producing, cytotoxic responses to IL-17-driven tissue repair and inflammation. In CRC, however, these subsets exhibit remarkable plasticity. In mouse models, for example, Vγ1+ and Vγ7+ IELs mediate potent antitumor immunity, whereas Vγ4+ and Vγ6+ LPLs can acquire IL-17-dependent pro-tumor functions. In contrast, human data depict a different balance. Across multiple cohorts, tumor-infiltrating γδ T cells, predominantly the Vδ1+ and Vδ2+ subsets, exhibit robust cytotoxic and IFN-γ-associated phenotypes. Meanwhile, the existence of bona fide IL-17-producing γδ T cells remains highly controversial. Higher γδ T-cell abundance correlates with better outcomes, even in tumors with defective HLA class I expression, where γδ T cells can mediate the therapeutic effects of PD-1 blockade. Emerging findings reveal subset heterogeneity, context-dependent functional states, and a crucial role for NK-receptor-mediated recognition, particularly via NKG2D. Together, these insights position γδ T cells as pivotal yet understudied regulators of CRC progression and immunotherapy responsiveness. Understanding their subset-specific biology could lead to next-generation γδ-based therapies tailored to the unique immunogenic constraints of colorectal cancer.