Neural regulation of immune evasion in breast cancer: a multiscale neuro–immune framework

Abstract

Background Immune escape remains a major barrier to durable benefit from immunotherapy in breast cancer, particularly in immune-cold tumors and those with an immune-excluded architecture. Emerging evidence from cancer neuroscience suggests that nerves are not passive bystanders of the tumor microenvironment, but active regulators of stromal remodeling, myeloid polarization, T-cell dysfunction, metastatic adaptation, and neuroendocrine stress biology. Main body We synthesize current evidence supporting a multiscale model of neuro–immune crosstalk in breast cancer. We first examine sympathetic innervation as an upstream coordinator of immunosuppressive signaling through β-adrenergic pathways that reshape myeloid compartments, lymphangiogenesis, and effector lymphocyte fitness. We then discuss sensory-nerve-driven immune exclusion, focusing on CGRP–CAF–ECM circuits and Substance P-associated inflammatory relays that stabilize prometastatic states. Next, we review direct nerve–tumor interfaces, including neurotransmitter-dependent synapse-like signaling, pseudo-synaptic coupling, extracellular-vesicle/TNT-mediated metabolic communication, and mitochondrial transfer, and evaluate their potential roles in immune resistance and metastatic competence. We further integrate these local interactions into a systems framework by considering tumor–brain–sympathetic feedback loops and neuroendocrine outputs that reset host immune thresholds while emphasizing the context-dependent nature of neural regulation across tumor types and microenvironmental states. Finally, we summarize neurodevelopmental programs co-opted during metastasis, discuss emerging technologies for neural phenotyping and spatial analysis, and highlight clinically actionable vulnerabilities, including β-blockade, CGRP-axis modulation, RET/TRK-targeted therapy, and phenotype-guided combination strategies. Conclusion This framework positions neural signaling as an upstream integrator of immune escape in breast cancer and suggests that neural biology may enable biologically informed stratification of immunotherapy-resistant tumors into distinct and targetable states.