α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.

Authors

Fei Li, Xiaorong Xie, Tongran Xu, Yu Tang, Yuting Xia, Yali Tang, Shijie Yuan, Mengdi Zhu, Xuwei Wu, Lan He, Shu-Hai Lin, Ran He

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 40. Pages e2606579123. Oct 06, 2026. Epub Sep 30, 2026.

Abstract

Tumor-associated macrophages (TAMs), the most abundant immune cell subset in the tumor microenvironment (TME), exhibit phenotypic plasticity and exert critical roles in tumor progression and antitumor immunity. Targeting TAM polarization has emerged as a promising strategy for cancer immunotherapy, yet the key regulators governing this process remain incompletely defined. Here, we identified α-aminobutyric acid (AABA) as a pro-tumor metabolite that drives M2-like polarization of TAMs to promote tumor progression. Mechanistically, AABA binds to asparagine synthetase (ASNS), reinforcing the mTORC2-IRF4 signaling axis to reprogram TAMs, switching macrophage metabolism from glycolysis to oxidative phosphorylation, a hallmark of pro-tumor M2-like phenotypes. Moreover, tumor-derived AABA was transported into macrophages by monocarboxylate transporters 1 and compromised the therapeutic efficacy of PD-1 checkpoint inhibition. Collectively, our findings uncover AABA as a previously unrecognized signaling metabolite to control TAM polarization, providing insights into the metabolic crosstalk within the TME and offering a potential therapeutic target to improve cancer immunotherapy outcomes.

PMID:
42814553
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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