Patient-derived organoid xenografts model esophageal cancer cachexia and enable assessment of anti-inflammatory drug repositioning.

Esophageal squamous cell carcinoma (ESCC) is highly associated with cancer cachexia, a wasting syndrome lacking effective treatments. Existing animal models fail to capture key clinical and biological features of this condition. Here, we established a panel of patient-derived organoid xenograft (PDOX) models that authentically replicate the heterogeneity of ESCC-associated cachexia in immunodeficient mice. PDOX lines exhibited slow tumor growth compared with traditional ESCC xenografts. Heterogeneous cachexia phenotypes in PDOX-bearing mice, as compared with non-tumor-bearing mice, including body weight loss, reduction in adipose tissue, reduced grip strength, and elevated pro-inflammatory cytokines, were observed. Using this platform, we tested two macrophage-targeting interventions: 10 mg/kg/day rosiglitazone, a PPAR-γ agonist, and 40 mg/kg/day pexidartinib (PLX3397), a CSF1R inhibitor. Both drugs significantly attenuated cachexia-associated functional decline and systemic inflammation. Transcriptomic analyses confirmed suppression of pro-cachectic cytokine signaling. This study presents a clinically relevant platform for preclinical cachexia research and supports macrophage modulation as a potential anti-cachexia strategy.