近日，美国俄克拉荷马大学李敏团队的最新研究探明了肿瘤-免疫-神经回路破坏癌症恶病质的能量稳态。2026年2月12日，国际知名学术期刊《癌细胞》发表了这一成果。

小组发现了一个未表征的肿瘤-免疫-神经回路驱动这些综合征，以生长和分化因子15 （GDF15）为中心。通过基因工程小鼠模型，研究人员发现GDF15的缺失可以防止胰腺癌、肺癌和皮肤癌的食欲减退、细胞萎缩和脂肪减少。单细胞RNA测序显示巨噬细胞是GDF15的主要来源，由肿瘤来源的集落刺激因子1 （CSF1）诱导。GDF15通过中枢神经系统增强肿瘤微环境中β-肾上腺素能信号，从而放大恶病质。GDF15中和抗体、抗CSF1R抗体或RET抑制剂破坏这一前馈回路，可显著减少恶病质和厌食症。这些发现揭示了一种连接肿瘤信号、巨噬细胞来源的GDF15和神经通路的非细胞自主机制，强调了肿瘤-免疫-神经三位一体是一个有希望的治疗靶点。

据介绍，癌症引起的恶病质和厌食症是许多癌症的衰弱并发症，但由于对其潜在机制的了解不足，有效的治疗仍然有限。

附：英文原文

Title: Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia

Author: Xiuhui Shi, Alex X. Arreola, Zhijun Zhou, Jingxuan Yang, Mingyang Liu, Yang Cai, Yu Ren, Hao Yuan, Qun Chen, Xinjie Chen, Xinyu Yang, Yimei Meng, Jingyi Wang, Wenyi Luo, Michael C. Rudolph, Rohan Varshney, Kar-Ming Fung, Chao Xu, Wei R. Chen, Michael S. Bronze, Lei Zheng, Yi-Ping Li, Courtney W. Houchen, Yuqing Zhang, Min Li

Issue&Volume: 2026-02-12

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.

DOI: 10.1016/j.ccell.2026.01.014

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(26)00053-X