Authors
Hailei Du, Tong Lang, Xiaoxue Zha, Chao Qu, Ling Chen, Shihua Yao, Xing Feng, Zhaohui Jin
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 33. Pages e2535328123. Aug 18, 2026. Epub Aug 10, 2026.
Abstract
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-1β neutralization, suppresses tumor progression and restores sensitivity to anti-PD-1 therapy. IL-1β further activates NF-κB and upregulates ALDH9A1, establishing a feedback ALDH9A1-IL-1β loop. Importantly, the ALDH9A1/IL-1β 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.
PMID:
42574617
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.
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