Nicotinic acetylcholine receptors as mediators of inflammation and autonomic neuropathy in breast cancer

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of breast cancer therapy, particularly with taxanes, and can persist long after treatment cessation. In parallel, breast cancer and its treatments can drive systemic inflammation; inflammatory mediators are increasingly linked to peripheral nociceptor sensitization, neuroimmune crosstalk, and impaired nerve repair. These converging processes support a framework in which CIPN reflects not only direct neurotoxicity but also inflammation-amplified mechanisms that sustain pain and delay recovery. Nicotinic acetylcholine receptors (nAChRs) constitute a neuroimmune signaling interface across neuronal, immune, and stromal compartments. In mechanistic models, α7 nicotinic acetylcholine receptor (α7nAChR) signaling mediates the efferent arm of the inflammatory reflex—the cholinergic anti-inflammatory pathway (CAP)—thereby constraining innate cytokine production and shaping inflammatory tone. In breast cancer systems, subtype-specific nAChR programs extend beyond neuroimmune regulation: α7-, α9-, and α5-containing receptors have been implicated in tumor cell survival and motility, fibroblast activation and stromal remodeling, angiogenic signaling, immune modulation, and therapy resistance. These effects appear highly context dependent, with ligand source (endogenous acetylcholine versus nicotine exposure) and microenvironmental state influencing downstream phenotypes. This review synthesizes clinical and experimental evidence on CIPN and autonomic dysfunction in breast cancer, evaluates inflammatory mechanisms that may govern neuropathy initiation and persistence, appraises vagal/CAP-related pathways while distinguishing preclinical from human data, and integrates subtype-resolved nAChR biology across neural, immune, and tumor compartments. We advance a bidirectional model in which chemotherapy-related nerve damage and tumor-associated inflammation reinforce one another via autonomic dysregulation, sustaining cytokine activity and symptom chronicity.