Neuron | 6-Hydroxydopamine promotes antitumor immunity through macrophage remodeling beyond sympathetic ablation | Wei Shi Lab

Summary

The sympathetic nervous system has emerged as a critical regulator of cancer progression, yet the underlying mechanisms remain unclear. Here, we compare genetic, pharmacological (6-hydroxydopamine [6-OHDA]), and surgical denervation in mouse breast cancer models. While all methods deplete sympathetic nerves, only 6-OHDA suppresses tumor growth, revealing a disconnect between sympathetic ablation and antitumor effect. Mechanistic investigations reveal that 6-OHDA suppresses tumor growth through immune activation rather than sympathetic ablation. 6-OHDA induces cancer cell interferon (IFN)-β production, which promotes monocyte differentiation into pro-inflammatory macrophages characterized by interferon-stimulated gene (ISG) expression. These ISG⁺ macrophages are essential for the expansion of type 1 T helper (T_H1) cells, which mediate prolonged tumor suppression. By contrast, sympathetic ablation alone does not affect macrophage differentiation or tumor growth. Our findings uncover an immunomodulatory function of 6-OHDA beyond its established neurotoxic activity and suggest the therapeutic potential of harnessing the macrophage-T_H1 axis for breast cancer.

DOI: https://www.cell.com/neuron/abstract/S0896-6273(26)00133-9