Commentary on "Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer".

Adoptive transfer of unmodified γδ T cells has shown limited clinical benefit, prompting a shift toward chimeric antigen receptor (CAR) engineering to enhance activation, persistence, and tumor specificity. CAR technology positions γδ T cells as promising carriers due to their innate-like cytotoxicity and HLA-independent recognition. Evidence from αβ CAR T-cell trials indicates that γδ CAR T cells can persist for months to years post-infusion, suggesting their potential contribution to long-term immune surveillance against cancer. Among γδ subsets, Vγ9Vδ2 T cells dominate peripheral blood and have been preferentially used for CAR engineering. Recent advances, however, enable the expansion of Vδ1 T cells, known for their tissue residency and resistance to exhaustion. In a key comparative study, Li et al benchmarked PSCA-targeted CARs in Vδ1, Vγ9Vδ2, and αβ T cells, showing similar short-term tumor control but distinct transcriptional and phenotypic programs. These findings highlight the need for subset-specific optimization of γδ CAR-T therapies. Early studies in hematologic malignancies could provide a practical proof of concept, before tackling the additional challenges of solid tumors. Such focused development may be essential to advance the γδ CAR-T field amid tightening industry investment.