Single-cell multiomics identifies an ALDH9A1-carnitine signaling axis driving resistance of NSCLC to immunotherapy

• 成果类型: Article
• 署名作者: Du, Hailei; Lang, Tong; Zha, Xiaoxue; Qu, Chao; Chen, Ling; Yao, Shihua; Feng, Xing; Jin, Zhaohui
• 署名单位: Shanghai Jiao Tong University; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Jilin University; Jilin University; Shanghai Jiao Tong University; Naval Medical University; Yale University; Yale University; Sichuan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2535328123
• 发表日期: 2026-08-18
• 页码: e2535328123
• 关键词: MDSCs; superenhancer; IL-1 beta; carnitine metabolism; cancer

摘要

Immunotherapy resistance remains a major barrier to achieving sustained patient improvement in non-small cell lung cancer (NSCLCs). Here, through integrating CODEX, metabolomics, CyTOF, ATAC-seq, and single-cell spatial transcriptomics from NSCLC tumors, we uncover an unrecognized role of ALDH9A1 in promoting resistance to anti-PD-1 therapy. In immunocompetent, but not immunocompromised mouse models, loss of ALDH9A1 markedly restrains tumor growth. This effect is accompanied by increased maturation of tertiary lymphoid structures and reduced accumulation of protumorigenic MDSCs within tumor immune microenvironment. Mechanistically, ALDH9A1-driven carnitine production elevates acetyl-CoA levels, remodels chromatin accessibility, and activates Il1b superenhancers in tumor cells, thereby promoting MDSC polarization and CD8+ T cell exhaustion. In vivo, genetic or pharmacological inhibition of ALDH9A1, or antibody-mediated IL-1 beta neutralization, suppresses tumor progression and restores sensitivity to anti-PD-1 therapy. IL-1 beta further activates NF-kappa B and upregulates ALDH9A1, establishing a feedback ALDH9A1-IL-1 beta loop. Importantly, the ALDH9A1/IL-1 beta axis is frequently hyperactivated in NSCLC patients and correlates with inferior responses to anti-PD-1 immunotherapy. Together, this study reveals a previously unappreciated NSCLC-specific immunoregulatory pathway and identifies ALDH9A1 as a promising therapeutic target for improving immunotherapy efficacy.