Faculty, Staff and Student Publications

Language

English

Publication Date

2-12-2026

Journal

Cancer Cell

DOI

10.1016/j.ccell.2026.01.014

PMID

41687610

PMCID

PMC12959363

PubMedCentral® Posted Date

3-5-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Cancer-induced cachexia and anorexia are debilitating complications across many cancers, yet effective treatments remain limited due to a poor understanding of the underlying mechanisms. Here, we identify an uncharacterized tumor-immune-neural circuit driving these syndromes, centered on growth and differentiation factor 15 (GDF15). Using genetically engineered mouse models, we find that loss of GDF15 protects against appetite loss, muscle wasting, and fat loss in pancreatic, lung, and skin cancers. Single-cell RNA sequencing reveals macrophages as a major source of GDF15, induced by tumor-derived colony-stimulating factor 1 (CSF1). GDF15 acts via the central nervous system to enhance β-adrenergic signaling in the tumor microenvironment, thereby amplifying cachexia. The disruption of this feedforward loop with GDF15-neutralizing antibody, anti-CSF1R antibody, or Rearranged during Transfection (RET) inhibitor markedly reduces both cachexia and anorexia. These findings reveal a non-cell-autonomous mechanism linking tumor signals, macrophage-derived GDF15, and neural pathways, highlighting the tumor-immune-neural triad as a promising therapeutic target.

Keywords

Tumor immune microenvironment, metabolic stress, muscle atrophy, norepinephrine, hormone

Published Open-Access

yes

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