Stress Biology in Cancer: Neuroendocrine–Immune Mechanisms Linking Tumor Progression to Translational Interventions

Abstract

Chronic stress-responsive signaling has emerged as a modifiable dimension of cancer biology by linking systemic neuroendocrine activation to tumor-cell adaptation, metabolic rewiring, immune suppression, tumor microenvironment remodeling, metastatic dissemination, and therapeutic resistance. Persistent activation of the sympathetic nervous system (SNS) and the hypothalamic pituitary adrenal (HPA) axis elevates catecholamines and glucocorticoids, which act through adrenergic receptors and the glucocorticoid receptor (GR) in tumor, stromal, vascular, and immune compartments. These canonical pathways regulate cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) signaling, GR-dependent transcription, angiogenic and inflammatory programs, extracellular matrix remodeling, myeloid polarization, T cell dysfunction, and resistance to cytotoxic and immune-based therapies. Beyond this classical SNS/HPA framework, emerging evidence indicates that cancer cells also engage noncanonical stress-adaptive hubs, including ion-channel signaling, redox-dependent mitochondrial responses, integrated stress-response pathways, prolactin/prolactin receptor signaling, and neurotrophin-mediated tumor–stroma–nerve crosstalk. These mechanisms are particularly relevant in highly plastic and immunogenic tumors such as melanoma, where stress adaptation intersects with immune visibility, metabolic flexibility, and therapy response. In this review, we synthesized how chronic stress signaling operates across systemic, tumor-intrinsic, immune, stromal, vascular, metabolic, and neural niches. We further mapped cancer-specific mechanisms across major malignancies and evaluated translational strategies, including β- and α-adrenergic blockade, GR modulation, stress-reducing behavioral interventions, and combination approaches with immunotherapy or standard anticancer regimens. Moreover, we discussed clinical challenges, including heterogeneity in stress exposure, context-dependent receptor activity, sex-specific stress biology, evidence maturity, and the need for biomarker-guided patient stratification. This integrated framework supports the development of mechanism-based stress-targeted adjunctive therapies in oncology.