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. 2025 Feb 26:S1550-4131(25)00018-X.
doi: 10.1016/j.cmet.2025.01.018. Online ahead of print.

MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia

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Free article

MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia

Qionghua Cui et al. Cell Metab. .
Free article

Abstract

Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.

Keywords: ACKR3; MIF; adipose remodeling; adipose stem and progenitor cells; cancer cachexia.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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