9-PAHSA orchestrates TCR-T cell fate to boost anti-tumor immunity
We identify the endogenous lipid 9-PAHSA as a potent enhancer of T cell anti-tumor function and stemness, validated in murine models and a clinical trial. Mechanistically, we identify ICAM2 as a direct surface sensor for 9-PAHSA and delineate a downstream signaling axis whereby the ICAM2-Ezrin-mTORC2 cascade drives FOXO1 O-GlcNAcylation at S318, facilitating its nuclear translocation to enact a stem-like transcriptional program. Translating this discovery, we engineered armored human TCR-T cells with potentiated ICAM2 expression, which achieve superior tumor control through their enhanced intrinsic efficacy and a remarkable ability to ignite a coordinated and durable host anti-tumor immune response. Our work establishes a new paradigm of metabolite-sensing in T cell biology and provides a compelling therapeutic strategy to potentiate cellular immunotherapy for intractable cancers. Overall design: Single-cell RNA sequencing (scRNA-seq) of the tumor microenvironment from a pancreatic cancer in situ model treated with or without the lipid metabolite 9-PAHSA. Following treatment, cells from dissociated whole tumors were isolated and analyzed using scRNA-seq. Five independent biological replicates (individual tumors) were analyzed per condition (vehicle control and 9-PAHSA treated).