Core Viewpoint - Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression. Recent studies indicate that sensory neurons play a significant role in the tumor microenvironment (TME) of TNBC, contributing to immune exclusion and tumor progression [2][4][15]. Group 1: Role of Sensory Neurons in TNBC - Sensory neurons are identified as the dominant neuron type in the TNBC ecosystem, comprising approximately 70% of the nerve fiber area in TNBC tissues, significantly higher than sympathetic and parasympathetic neurons [7]. - Patients with positive perineural invasion (PNI) exhibit worse prognoses, including higher rates of lymph node and bone metastases, alongside reduced immune cell infiltration and increased collagen deposition in the TME [7]. Group 2: Mechanism of Immune Exclusion - The study outlines a clear signaling pathway where tumor cells secrete nerve growth factor (NGF) to attract sensory neurons, which then release the neuropeptide CGRP, activating cancer-associated fibroblasts (CAFs) [9]. - The CGRP-RAMP1 signaling axis promotes the transformation of CAFs into myofibroblasts, leading to significant collagen deposition that physically obstructs immune cell infiltration [9]. Group 3: Therapeutic Strategies - Targeting the CGRP-RAMP1 signaling axis with the FDA-approved migraine medication Rimegepant shows promise in TNBC treatment, as it significantly inhibits tumor growth, reduces collagen deposition, and enhances the infiltration of immune cells like CD8+ T cells [10][13]. - Clinical data suggest that high CGRP expression correlates with poorer prognosis and reduced response to immunotherapy, indicating its potential as a biomarker for selecting patients who may benefit from combination therapies [13]. Group 4: Conclusion and Future Directions - The findings reveal that sensory neurons are not mere bystanders but active participants in tumor progression by facilitating immune evasion in TNBC [15]. - The research opens new avenues for cancer neurobiology, emphasizing the need for multi-faceted approaches that target both cancer cells and their surrounding ecosystems [16].