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.