This article identifies a self-perpetuating tumor-immune-neural circuit that drives cancer cachexia, a debilitating syndrome of muscle and fat wasting. The study reveals that tumors secrete CSF1, which triggers macrophages to produce the hormone GDF15. This hormone acts on the brainstem to activate the sympathetic nervous system, which in turn releases norepinephrine that further stimulates tumor cells to produce more CSF1 via a ZIP4-ZFP64 signaling pathway. This feedback loop disrupts systemic energy balance, leading to anorexia and severe tissue loss in pancreatic, lung, and skin cancers. Experimental results show that pharmacologically blocking this axis with anti-GDF15, anti-CSF1R, or RET inhibitors effectively reverses wasting symptoms. Consequently, targeting this tripartite interaction offers a promising therapeutic strategy for improving the quality of life and survival of patients with advanced cancer.

References:

• Shi X, Arreola A X, Zhou Z, et al. Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia[J]. Cancer cell, 2026.