Cancer cachexia is a devastating wasting syndrome that impacts patients' quality of life and limits the efficacy and options of therapies. Adipose tissue shrinkage is a hallmark of pre-cachexia stage, precedes the onset of skeletal muscle atrophy. In contrast to physiological fat loss induced by exercise, cachexia-associated adipose wasting is characterized by involuntary, progressive, and irreversible depletion, coupled with adipose tissue inflammation and fibrosis. However, the molecular differences between physiologically regulated and pathologically driven fat loss remain poorly understood. Elucidating the molecular mechanisms regulating cachexia-induced adipose remodeling is critical for the identification of actionable therapeutic targets in cancer cachexia.

We generated mouse models including exercise, subcutaneous tumor transplantation, orthotopic lung cancer, and genetically engineered systems. Subcutaneous adipose tissues from healthy individuals and cancer patients were collected for single-cell RNA sequencing (scRNA-seq). Phosphoproteomics, proteomics, and bulk RNA sequencing were performed to identify cachexia-associated signaling pathways.

Our results showed that adipogenesis was impaired in cancer cachexia but not in exercise-induced weight loss. In tumor-bearing mice, adipose fibrosis and inflammation increased, and adipogenesis-related genes were downregulated. scRNA-seq revealed the proportion of fibro-inflammatory progenitor cells (FIPs) increased while preadipocytes decreased in adipose stem and progenitor cells (ASPCs) of cachectic mice. Tumor-secreted macrophage migration inhibitory factor (MIF) was identified as a key factor in regulating ASPCs cell fate. MIF levels were elevated in cachexia and negatively correlated with body weight loss. Conversely, in exercise models, MIF levels moderately decreased. Atypical chemokine receptor 3 (ACKR3) on FIPs was the main receptor for MIF. MIF-ACKR3 signaling activated the ERK1/2-NFκB pathway through Gβγ-GRK2, repressing adipogenesis and promoting inflammation and fibrosis. Inhibition of MIF by gene ablation or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, alleviated cachectic manifestations, protected adipose tissue and improved muscle mass and function. However, the functions of ACKR3 in gonadal/brown adipose tissue, the impact of MIF on skeletal muscle atrophy need further investigation.

Collectively, our findings identifies adipogenesis is a key discriminator between cachexia-induced adipose wasting and physiologically regulated fat loss. The MIF-ACKR3 signaling axis was identified as the principal regulatory pathway, serving as a critical link between tumor-derived signals and pathological adipose tissue depletion in cachexia. Targeting MIF-ACKR3 may be a promising therapeutic strategy for cancer cachexia.