Evidence from tumor neuroscience and clinical observations have implicated the autonomic nervous system (ANS) in breast cancer pathobiology. Sympathetic activation (norepinephrine/β‑adrenergic signaling) aligns with pro‑angiogenic, pro‑invasive programs and distant spread, whereas increased vagal activity is associated with an anti‑inflammatory state and restraint of progression. The present review summarizes mechanistic, translational and clinical data supporting a bidirectional regulatory model and evaluates a variety of ANS‑targeted strategies, including β‑adrenergic modulation, non‑invasive vagus nerve stimulation and related neuromodulatory approaches. Whilst biologic plausibility is strong, clinical evidence remains heterogeneous and limited by study design. To the best of our knowledge, no adequately powered randomized trials have demonstrated sufficient survival benefits. The present review outlines principles for standardized autonomic phenotyping (such as heart rate variability), candidate patient selection and trial endpoints to test whether ANS modulation can improve recurrence, metastasis, toxicity and quality‑of‑life outcomes. Through integrating convergent evidence and articulating testable hypotheses, the present review provides an ANS‑informed framework to guide future breast cancer research and care.
