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Single-cell multiomics identifies an ALDH9A1-carnitine signaling axis driving resistance of NSCLC to immunotherapy
Hailei Du1, Tong Lang2, Xiaoxue Zha3,4
1Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
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.
Insights
Aldehyde dehydrogenase 9A1 (ALDH9A1) drives resistance to anti-PD-1 immunotherapy in non-small cell lung cancer (NSCLC). Inhibiting ALDH9A1 or IL-1β restores anti-tumor immunity and improves treatment response.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Immunotherapy resistance is a significant challenge in non-small cell lung cancer (NSCLC) treatment.
- Identifying novel targets to overcome this resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of ALDH9A1 in anti-PD-1 therapy resistance in NSCLC.
- To elucidate the underlying mechanisms of ALDH9A1-mediated immune evasion.
- To explore ALDH9A1 as a potential therapeutic target.
Main Methods:
- Integrated analysis of CODEX, metabolomics, CyTOF, ATAC-seq, and single-cell spatial transcriptomics in NSCLC tumors.
- Utilized immunocompetent and immunocompromised mouse models.
- Investigated genetic and pharmacological inhibition strategies.
- Assessed IL-1β neutralization and NF-κB pathway activation.
Main Results:
- ALDH9A1 promotes NSCLC resistance to anti-PD-1 therapy by increasing protumorigenic myeloid-derived suppressor cells (MDSCs) and CD8+ T cell exhaustion.
- ALDH9A1-driven carnitine production elevates acetyl-CoA, remodels chromatin, and activates IL-1β superenhancers, fostering MDSC polarization.
- Inhibition of ALDH9A1 or IL-1β suppressed tumor growth and restored anti-PD-1 sensitivity.
- A feedback loop between ALDH9A1 and IL-1β was identified, frequently hyperactivated in NSCLC patients.
Conclusions:
- ALDH9A1 plays a critical role in NSCLC immune evasion and immunotherapy resistance.
- The ALDH9A1-IL-1β axis represents a novel, NSCLC-specific immunoregulatory pathway.
- Targeting ALDH9A1 offers a promising strategy to enhance anti-PD-1 immunotherapy efficacy in NSCLC.
