In Vivo CRISPR Screens Identify SLC1A5 as a Metabolic Checkpoint for Cancer Immunotherapy

Here, using in vivo metabolic CRISPR screening under distinct immune pressures, we identified tumor cell–derived solute carrier family 1 member 5 (SLC1A5) as a critical metabolic node that sustains an immunosuppressive tumor microenvironment (TME). SLC1A5-mediated glutamine metabolism in tumor cells modulates CD8 T cell infiltration and effector function, reshaping tumor response to immune checkpoint blockade therapy.

Mechanistically, glucose deprivation up-regulated SLC1A5 isoforms in tumor cells, enhancing glutamine uptake and metabolic flux remodeling to reset intracellular metabolic homeostasis. This program suppressed inflammatory tumor cell differentiation characterized by cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway activation, reducing interferon-β secretion and impairing CD8 immunity. These findings define a glutamine-fueled metabolic program as a critical barrier to tumor immunogenicity, positioning SLC1A5 as a metabolic immune checkpoint with therapeutic relevance.