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.