Neural signals can significantly influence cancer prognosis. However, how cancer cells may proactively modulate the nervous system to benefit their own survival is incompletely understood. In this study, we report an overlapping pattern of brain responses, including that in the paraventricular nucleus of the hypothalamus, in multiple mouse models of peripheral cancers. A multi-omic screening then identifies leukemia inhibitory factor (LIF) and galectin-3 (Gal3) as the key cytokines released by these cancer cell types to trigger brain activation. Importantly, increased plasma levels of these two cytokines are observed in patients with different cancers. We further demonstrate that pharmacologic or genetic blockage of cancer cell-derived LIF or Gal3 signaling abolishes the brain responses and strongly inhibits tumor growth. In addition, ablation of peripheral sympathetic actions can similarly restore antitumor immunity. These results have elucidated a novel, shared mechanism of multiple cancer cell types hijacking the nervous system to promote tumor progression.

神经信号可以显着影响癌症的预后。然而，癌细胞如何主动调节神经系统以利于自身生存尚不完全清楚。在这项研究中，我们报告了多种外周癌症小鼠模型中大脑反应的重叠模式，包括下丘脑室旁核的反应模式。然后，多组学筛选确定白血病抑制因子 (LIF) 和半乳糖凝集素 3 (Gal3) 是这些癌细胞类型释放的触发大脑激活的关键细胞因子。重要的是，在患有不同癌症的患者中观察到这两种细胞因子的血浆水平升高。我们进一步证明，药物或基因阻断癌细胞衍生的 LIF 或 Gal3 信号传导可以消除大脑反应并强烈抑制肿瘤生长。此外，周围交感神经活动的消融同样可以恢复抗肿瘤免疫力。这些结果阐明了多种癌细胞类型劫持神经系统促进肿瘤进展的一种新颖的、共享的机制。