Tumor-derived RAC1^A159V mutation promotes an immunosuppressive microenvironment that represses response to immune checkpoint inhibitor.

ABSTRACT: RAC1^A159V is a hotspot mutation associated with poor prognosis in several cancers. By gene editing, we generated endogenous homozygous and heterozygous RAC1^A159V mutations, which result in up-regulated RAC1 activity and mammalian target of rapamycin (mTOR) signaling. RAC1^A159V tumors grow faster than RAC1^WT tumors in immune-proficient mice and are resistant to anti-programmed death protein 1 (PD1). Flow cytometry and scRNA-seq analyses reveal that RAC1^A159V cells form "cold" tumors with an immunosuppressive microenvironment and reduced tumor-immune cell interactions. Mechanistically, RAC1^A159V up-regulates glycosphingolipid biosynthesis to activate mTORC1 signaling in tumor cells, which in turn increases glycolysis, impairs

SUBMITTER: Cai M 

PROVIDER: S-EPMC12571076 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature