Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia
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.
Authors
- Yimei Meng (ORCID: https://orcid.org/0000-0001-7489-5634)
- Jingxuan Yang (ORCID: https://orcid.org/0000-0003-3265-161X)
- Kar‐Ming Fung (ORCID: https://orcid.org/0000-0002-4623-9469)
- Xinjie Chen (ORCID: https://orcid.org/0000-0002-5492-225X)
- Courtney W. Houchen (ORCID: https://orcid.org/0000-0003-2487-5242)
- Mingyang Liu (ORCID: https://orcid.org/0000-0001-9121-2591)
- Wenyi Luo (ORCID: https://orcid.org/0000-0003-1160-2093)
- Rohan Varshney (ORCID: https://orcid.org/0000-0002-8580-3675)
- Michael S. Bronze (ORCID: https://orcid.org/0000-0002-8770-0872)
- Xiuhui Shi
- Zhijun Zhou
- Michael C. Rudolph
- Hao Yuan
- Wei R. Chen
- Chao Xu
- Jingyi Wang
- Yuqing Zhang
- Yu Ren
- Alex X. Arreola
- Qun Chen
- Xinyu Yang
- Yi-Ping Li
- Min Li
- Lei Zheng
- Yang Cai
Institutions
- Johns Hopkins University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Oklahoma City University (US)
- Yale University (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- University of Oklahoma Health Sciences Center (US)
- University of Oklahoma (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Cancer Cell
- Published
- 2026-02-01
- DOI
- https://doi.org/10.1016/j.ccell.2026.01.014
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University of Oklahoma
- William and Ella Owens Medical Research Foundation
- National Institutes of Health
- Stephenson Cancer Center
- National Cancer Institute
- National Institute of General Medical Sciences