Abstract
Although cancer immunotherapy has recently revolutionized treatment, the low response rate to existing immune checkpoint blockade (ICB) underscores the need for new druggable targets. Here, we find that SOAT1 is selectively expressed in cancer stem cell (CSC) and pharmacological inhibition with STK results in robust anti-tumor effects across various preclinical mouse models, including colon, liver, lung, breast, and melanoma cancer, with low toxicity. Mechanistically, treatment with STK (or gene knockdown of Soat1) induces the release of 20(S)-Hydroxycholesterol (20SOHC) from the tumor cells, and downstream activation of the trans-cellular 20SOHC (tumor)- GPR132 pathway in regulatory T cell (Treg), ultimately resulting in the suppression of Treg functions and enhanced dendritic cells and cytotoxic CD8+ T cell responses. Importantly, STK treatment synergizes with anti-PD-1 or anti-CTLA-4 ICB therapy. Thus, our findings identify SOAT1 as a CSC metabolism checkpoint that facilitates immune evasion and SOAT1 inhibition as a promising strategy for advanced cancer immunotherapy.
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Data availability
The single-cell RNA-sequence raw data are deposited at Gene Expression Omnibus (GEO) at GSE286015 (scRNA-seq for Hepatocellular carcinoma, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE286015) and GSE286092 (scRNA-seq for Lung carcinoma, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE286092). The Bulk RNA-sequence raw data are deposited at Gene Expression Omnibus (GEO) at GSE309517. All data are included in the Supplementary Information or available from the authors, as are unique reagents used in this Article. Source data are provided with this paper.
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Acknowledgments
The State Key Laboratory of Genetic Engineering (Fudan University, Shanghai, China) and the Animal Facility of the Institute of Development Biology (Fudan University, Shanghai, China) are appreciated for their technological assistance. This work was supported by the National Key R&D Program of China (Grant No. 2024YFA1306000 to S.X.H and 2023YFA1800202 to S.X.H) and the National Natural Science Foundation of China (Grant No. 8245010 to S.X.H).
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Yahui Ding: Writing original draft, Visualization, Investigation, Formal analysis, Data curation, Conceptualization, Software, Resources. Wanqi Fang: Writing original draft, Investigation, Formal analysis, Data curation, Conceptualization, Resources. Ruiqing Xiang: Investigation, Formal analysis. Haitao Liu: Investigation, Data curation. Menglin Huang: Formal analysis, Data curation. Yingran Shen: Formal analysis, Data curation. Ying Chen: Formal analysis, Data curation. Guohao Wang: Formal analysis, Data curation. Zhaocai Zhou: Supervision, Project administration. Yun Ling: Supervision, Project administration. Ling Sun: Supervision, Project administration, Funding acquisition, Conceptualization. Yuetong Wang: Writing review&editing, Validation, Project administration, Methodology, Funding acquisition, Conceptualization. Steven X. Hou: Writing-review & editing, Supervision, Project administration, Funding acquisition, Conceptualization. All authors have reviewed and approved the submission. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work, ensuring integrity and accuracy.
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Ding, Y., Fang, W., Xiang, R. et al. Inhibition of the cancer stem cell immune checkpoint SOAT1 suppresses regulatory T cell functions through a trans-cellular 20(S)-Hydroxycholesterol-GPR132 pathway in mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69305-3
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DOI: https://doi.org/10.1038/s41467-026-69305-3
