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

Area of Science:

• Oncology
• Immunology
• Metabolic pathways

Background:

• Tumor cells rely on branched-chain amino acids, but their downstream metabolites, branched-chain α-keto acids (BCKAs), are understudied in cancer.
• The role of BCKAs in the tumor microenvironment (TME) and their impact on immune cells remain largely unknown.

Purpose of the Study:

• To investigate the role of tumor-derived BCKAs in reprogramming the TME.
• To identify the molecular mechanisms by which BCKAs influence tumor progression and immune suppression.

Main Methods:

• Utilized clinical samples and genetically engineered mouse tumor models.
• Performed genome-wide CRISPR screening to identify molecular targets of BCKAs.
• Investigated the interaction between BCKAs and Notch2 signaling in vivo and in vitro.

Main Results:

• Demonstrated active secretion of BCKAs from tumor cells into the TME.
• Showed that BCKAs reprogram tumor-associated macrophages (TAMs) to promote tumor progression.
• Identified Notch2 as a direct molecular target of BCKAs, with BCKAs stabilizing cleaved Notch2 and activating Notch signaling.
• Confirmed that mutation of the BCKA-binding site in Notch2 abrogates these effects.

Conclusions:

• BCKAs are secreted signaling metabolites that reprogram TAMs and foster an immunosuppressive TME.
• BCKAs mediate tumor immunosuppression through direct sensing and activation of Notch2 signaling.