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

Chronic stress activates the sympathetic nervous system (SNS) and has been linked to cancer progression, yet the role of SNS in cancer remains controversial. 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. Conversely, genetic sympathectomy fail to alter immune infiltration, distinguishing 6-OHDA's immune-modulatory effect from sympathetic ablation. Our findings reveal an unexpected off-target effect of 6-OHDA that suppresses tumor growth by modulating the immune microenvironment, which is independent of sympathetic ablation.