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

The metabolic basis of tumor-associated macrophages (TAMs)-driven immune checkpoint blockade (ICB) resistance remains poorly understood. Here, in patients with immunotherapy-resistant cancer, we identify significant enrichment of TAMs marked by elevated aldehyde dehydrogenase 2 (ALDH2) expression. Myeloid-restricted ALDH2 ablation converts TAMs from a pro-tumorigenic phenotype 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, 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 promoter region. Subsequent CXCL9 derepression in TAMs facilitates persistent CD8⁺ T cell infiltration and enhances their cytotoxic effector functions. Clinical validation confirms that pronounced ALDH2 elevation in TAMs correlates with accelerated immunotherapy failure. Therapeutically, as a clinically approved ALDH2 inhibitor, disulfiram exerts its anti-tumor effect by selective reprogramming TAMs metabolism. Overall, our findings delineate a druggable ALDH2-metabolism-epigenetics axis in antitumor immunity, nominating ALDH2 inhibition for combination immunotherapy.