# Neuro-immune crosstalk in breast cancer: molecular mechanisms from stress signals to immune escape

## TL;DR

This paper explores how the nervous system influences breast cancer progression and immune evasion through stress signals and neuro-immune interactions.

## Contribution

The paper provides a comprehensive overview of how different nerve types modulate breast cancer progression and immune responses.

## Key findings

- Elevated nerve fiber density in breast cancer tissues correlates with increased invasiveness and poor prognosis.
- Sympathetic signaling promotes tumor growth and immune suppression, while parasympathetic signaling may inhibit tumor progression.
- Neuro-immune interactions represent a promising target for adjuvant breast cancer therapy.

## Abstract

Breast cancer (BC) exhibits marked biological heterogeneity and remains a major cause of cancer-related death in women. With advances in molecular subtyping and tumor microenvironment research, the nervous system has emerged as an important regulator of BC initiation, progression, and metastasis. Tumor-associated nerves influence cancer not only locally through sympathetic, parasympathetic, and sensory innervation, but also systemically by modulating immunity via psychological stress, circadian rhythms, and neuroendocrine pathways.

Increasing evidence shows that nerve fiber density is elevated in BC tissues and correlates with greater invasiveness and poorer prognosis. The sympathetic nervous system promotes tumor growth, angiogenesis, and metastasis mainly through β-adrenergic signaling and suppression of anti-tumor immunity. Chronic psychological stress further enhances tumor-promoting immune changes through sustained neuroendocrine activation. In contrast, parasympathetic signaling may exert inhibitory effects on tumor progression, while sensory nerves and neuropeptides display context-dependent roles in inflammation, pain, and immune regulation. Moreover, circadian rhythm disruption and reduced melatonin impair tumor immune surveillance. Clinical and retrospective studies suggest that neural-targeted interventions, such as β-blockers and psychological therapies, may improve the immune microenvironment and clinical outcomes in BC.

The nervous system plays a crucial role in shaping the BC microenvironment and promoting immune escape through complex, multi-level mechanisms. Different types of nerves exert distinct effects on tumor progression. Targeting neuro-immune interactions may therefore offer a promising strategy for adjuvant BC therapy.

A schematic diagram of the interaction between the nervous system, tumors and immune cells in BC.Diagram illustrating how chronic stress and neuro-immune interactions affect breast cancer progression, showing sympathetic and parasympathetic neural pathways, their impact on immune cells, tumor proliferation, nerve recruitment, and the balance between immune escape, tumor progression, and anti-tumor immunity.

A schematic diagram of the interaction between the nervous system, tumors and immune cells in BC.