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

GALE is identified as a tumor-intrinsic checkpoint that restricts Vγ9Vδ2 T cell-mediated killing, with GALE loss potentiating antitumor activity in multiple mouse models and organoids.

• Why it matters: Vγ9Vδ2 T cells can target tumors without HLA, but their therapeutic efficacy is limited, and the tumor-intrinsic mechanisms that restrain their killing are unclear.
• What they did: A genome-wide CRISPR screen pinpointed UDP-galactose 4-epimerase (GALE); mechanistic work shows GALE supports complex N-glycosylation of CD155 and CEACAM1, promoting TIGIT and TIM3 engagement while limiting CD155–CD226 binding.
• The result: In multiple mouse models and colorectal cancer patient-derived organoids, GALE loss potentiates Vγ9Vδ2 T cell-mediated tumor killing, suggesting GALE and its CD155/CEACAM1 receptor-ligand interactions as therapeutic targets.

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