Peripheral nerve injury-induced remodeling of the tumor-associated macrophages promotes immune evasion in breast cancer

Abstract Background Peripheral nerve damage is intricately linked to the progression of various solid tumors. However, its effect on antitumor immunity and precise underlying mechanisms remain poorly understood. This study aimed to elucidate the effect of peripheral nerve damage and its subsequent immune-modulating effects influence on breast cancer progression. Methods We analyzed nerve injury markers in the TCGA-BRCA database and clinical samples. In vivo experiments were conducted using orthotopic breast cancer models with chemical sympathetic denervation (6-OHDA) or nerve lysate/neurofilament light chain (NFL) treatment, where NFL was identified as a key effector molecule through mass spectrometry screening. The tumor microenvironment was evaluated by flow cytometry, multiplex immunohistochemistry, and single-cell RNA sequencing. In vitro co-culture systems were established to investigate the effects of NFL on macrophages and CD8 + T cells, with transcriptomic profiling revealing that NFL-activated macrophage supernatants induced CD8 + T cell senescence via NF-κB signal pathway activation. Results Peripheral nerve injury was associated with poor prognosis and immune evasion in breast cancer patients. In mouse models, chemical sympathectomy (6-OHDA) and nerve lysates injection both accelerated tumor growth, suggesting that nerve damage promotes immune escape. Single-cell RNA sequencing (scRNA-seq) further revealed that nerve injury increased tumor-associated macrophages (TAMs) proportion by promoting TAMs proliferation and attracting macrophages. The key effector molecule of nerve lysates neurofilament light chain (NFL) was identified with the TAMs proliferation effect, and intratumoral NFL administration recapitulated the pro-tumor effects of nerve damage and perfomed the same immune-modulating effects as 6-OHDA and nerve lysates. Importantly, NFL-induced TAM enrichment and remodeling promoted CD8 + T cell senescence, as evidenced by transcriptomic analysis showing NF-κB pathway activation and verified with NF-κB inhibitor (BAY 11-7082) in vitro, resulting in breast cancer immune escape. Conclusion These findings underscore the critical role of peripheral nerve injury in reshaping the interplay between TAMs and antitumor immunity, via NFL-driven NF-κB activation and T cell dysfunction. Suggesting that neuroprotection could serve as a promising strategy to restore anticancer immunosurveillance.