Tumor-derived branched-chain α-keto acids activate Notch signaling in tumor-associated macrophages to limit immunity.

Tumor cells are highly dependent on branched-chain amino acids, which can activate mechanistic target of rapamycin complex 1, but the downstream catabolite branched-chain α-keto acids (BCKAs) are not well studied in this context. Here, using clinical samples and genetically engineered mouse tumor models, we showed that tumor-derived BCKAs are secreted actively into the tumor microenvironment (TME) where they reprogram tumor-associated macrophages (TAMs) to promote tumor progression. Through genome-wide CRISPR screening, we identified Notch2 as a direct molecular target of BCKAs. BCKAs activate Notch signaling by binding to and stabilizing cleaved Notch2, functionally reprogramming TAMs and fostering an immunosuppressive TME. Mutation of the BCKA-binding site in Notch2 abolishes this effect in vivo. Together, these findings identify BCKAs as signaling metabolites that mediate tumor immunosuppression through direct sensing by Notch2.