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

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.

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.

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.