Work

Macrophage ALDH2 drives immunotherapy resistance by silencing CXCL9 through metabolic-epigenetic crosstalk

Year: 2026

Type: article

Abstract: The metabolic basis of tumor-associated macrophage (TAM)-driven immune checkpoint blockade (ICB) resistance remains poorly understood. In immunotherapy-resistant cancer patients, we identified significant enrichment of TAMs marked by elevated aldehyde dehydrogenase 2 (ALDH2) expression. Myeloid-restricted ALDH2 ablation converts TAMs from protumorigenic collaborators to immunostimulatory regulators, concomitantly amplifying CD8+ T cell infiltration and cytotoxicity to improve ICB responsiveness. Mechanistically, ALDH2 deficiency induces the intracellular accumulation of reactive aldehydes, specifically 4-hydroxynonenal (4-HNE), which activates the PI3K-Akt signaling axis. This pathway phosphorylates and suppresses Ezh2 methyltransferase activity, leading to the erosion of H3K27me3-mediated epigenetic silencing at CXCL9 enhancer regions. Subsequent CXCL9 derepression facilitates persistent CD8+ T cell infiltration and enhances their cytotoxic effector functions. Clinical validation confirmed that pronounced ALDH2 elevation in TAMs correlates with accelerated immunotherapy failure. Therapeutically, as a clinically approved ALDH2 inhibitor, disulfiram (DSF) exerts its anti-tumor effect by selective reprogramming TAM metabolism. Our data delineate a druggable ALDH2-metabolism-epigenetics axis in antitumor immunity, nominating ALDH2 inhibition for combination immunotherapy.

Source: Nature Communications

DOI: 10.1038/s41467-026-73234-6