6-Hydroxydopamine promotes antitumor immunity through macrophage remodeling beyond sympathetic ablation

To investigate sympathetic regulation of cancer, we use genetic, pharmacological (6-hydroxydopamine, 6-OHDA) and surgical sympathetic ablation in a transgenic mouse model of breast cancer. Although all methods effectively deplete sympathetic nerves, only 6-OHDA, a neurotoxin targeting catecholaminergic neurons, suppresses tumor growth.

Mechanistically, 6-OHDA promotes monocyte recruitment and their differentiation into pro-inflammatory CD64⁺Sca-1⁺ macrophages (MoMacs) through type I interferon signaling. These MoMacs function as antigen-presenting cells, stimulating type 1 T helper (TH1) cells to combat tumor growth. Depletion of MoMacs abolishes both TH1 response and 6-OHDA’s tumor-suppressive effect.