GALE is a tumor-intrinsic checkpoint of Vγ9Vδ2 T cell-mediated killing.

Vγ9Vδ2 T cells mediate HLA-independent targeting of tumor cells, offering unique opportunities for cancer immunotherapy, yet their therapeutic efficacy remains limited. Here, using a genome-wide CRISPR screen, we identify UDP-galactose 4-epimerase (GALE) as a tumor-intrinsic checkpoint that restricts Vγ9Vδ2 T cell-mediated killing. GALE is a key nucleotide-sugar metabolic enzyme that controls the interconversion of UDP-galactose and UDP-glucose, thereby supporting protein glycosylation and cell-surface glycan remodeling. Mechanistically, GALE promotes complex N-glycosylation of CD155 and CEACAM1, favoring their engagement with the inhibitory receptors TIGIT and TIM3, respectively, while limiting CD155 binding to the activating receptor CD226.

GALE loss potentiates Vγ9Vδ2 T cell-mediated tumor killing in multiple mouse models and colorectal cancer patient-derived organoids. Together, these findings reveal how nucleotide-sugar metabolism shapes tumor-immune communication through complex N-glycan remodeling and identify GALE and its downstream receptor-ligand interactions as potential therapeutic targets for enhancing Vγ9Vδ2 T cell antitumor activity.