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<p>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<sup>+</sup> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Huiying Fang,
  • Jiazheng Sun,
  • Qian Xiao,
  • He Ren,
  • Yuru Chen,
  • Jiazhou Liu,
  • Daqiang Song,
  • Tiantian Chen,
  • Linling Wu,
  • Pin Wang,
  • Jian Yue,
  • Xiaoyu Wang,
  • Qilin Yang,
  • Yuxian Wei,
  • Huimin Du,
  • Weiyan Peng,
  • Zhu Qiu,
  • Li Zhang,
  • Jingyuan Wan,
  • Tong Liu,
  • Guosheng Ren,
  • Hongzhong Li

摘要

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.