Sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling and synergizes immunotherapy in triple-negative breast cancer.

Objective: Triple-negative breast cancer (TNBC) has shown resistance to immunotherapy. Stimulating ProkR2-bearing sensory neurons of the sciatic nerve has been reported to regulate immune function by catecholamine release through the vagal-adrenal axis. We aimed to investigate the impact of sciatic nerve stimulation on anti-tumor immune responses and immunotherapy efficacy in TNBC.

Methods: We implemented ProkR2-bearing neuron stimulation in a TNBC mouse model. Single-cell RNA sequencing, flow cytometry, and immunohistochemistry were employed to uncover alterations in the tumor immune microenvironment. Immune cell depletion and receptor inhibitors were used to verify the cellular and molecular mechanisms by which neurostimulation regulates anti-tumor immunity.

Results: Sciatic nerve stimulation inhibited 4T1 tumor growth by activating natural killer (NK) cells in the tumor microenvironment. The D1-like dopamine receptor-cAMP-PKA-CREB signaling pathway is essential for enhanced NK cell cytotoxicity and tumor inhibition induced by neurostimulation. Neurostimulation upregulated tumor PD-L1 expression through IFN-gamma pathway. Combining sciatic nerve stimulation with anti-PD-1 therapy resulted in superior tumor control compared to either approach alone and demonstrated good safety.

Conclusions: This research addresses a long-standing gap in understanding neuro-immune regulation in cancer treatment, presenting a promising strategy for overcoming immunoresistance in TNBC.