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A novel target to turn cold tumors into hot tumors: lysosomal 25-hydroxycholesterol activates AMPKα and immunosuppressive tumor-associated macrophages

Cellular & Molecular Immunology (2024)Cite this article

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Fehleisen and Busch, two physicians from Germany, independently observed significant tumor regression following erysipelas infection in the late 19th century, and they provided the earliest scientific evidence for tumor immunotherapy [2]. To date, immunotherapy has emerged as a focal point in cancer treatment, with the concept of the TME pivotal for understanding cancer initiation and progression [3]. Among the diverse immune cell populations within tumors, tumor-associated macrophages (TAMs) play a crucial role in fostering tumor progression by shaping the TME by promoting angiogenesis, extracellular matrix remodeling, and immunosuppression [4]. Targeting TAMs thus represents a key strategy to convert “cold tumors”, characterized by immunosuppressive myeloid-derived suppressor cells, into “hot tumors”, infiltrated by T cells.

Recent advancements in single-cell multiomics technologies have allowed the discovery of distinct transcriptional and metabolic characteristics among various macrophage subsets within the TME [5]. Understanding this complex interplay between tumor cells and macrophages has propelled the development of effective clinical treatment strategies. These include targeting colony-stimulating factor 1 receptor to impede TAM recruitment and activating inflammatory signaling pathways or targeting myeloid checkpoints and regulators to promote macrophage polarization to repolarize TAMs from an immunosuppressive phenotype toward an inflammatory phenotype. The ability of TAMs to induce this phenotypic switch has become a prominent focus in cancer therapy research [4].

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Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (Project: 32371243; 32171168; 32350610248).

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  1. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Shuangshuang Liu, Jiaqi Wu, Xiao Tong & Li-Hao Huang

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  1. Shuangshuang Liu
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  2. Jiaqi Wu
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Correspondence to Li-Hao Huang.

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Liu, S., Wu, J., Tong, X. et al. A novel target to turn cold tumors into hot tumors: lysosomal 25-hydroxycholesterol activates AMPKα and immunosuppressive tumor-associated macrophages. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01171-9

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