Chronic stress and the nervous system as active architects of tumor evolution and microenvironment remodeling

Chronic stress is increasingly recognized as an important factor influencing cancer progression through sustained activation of neural and neuroendocrine signaling. Within the tumor microenvironment, the nervous system has emerged as an important regulatory component alongside immune, stromal, vascular, and metabolic elements. Rather than acting as passive bystanders, tumor-associated nerves and cancer cells engage in reciprocal interactions, whereby neural inputs regulate tumor progression while tumors promote neurogenesis, nerve infiltration, and neural remodeling. Through autonomic signaling, neurotransmitters, neurotrophic factors, axon-guidance programs, and synapse-like communication, the nervous system can influence tumor cell plasticity, invasion, microenvironmental remodeling, and therapeutic response. Preclinical studies indicate that chronic stress and neural signaling can promote tumor growth, metastasis, and reduced treatment responsiveness in specific experimental settings. Patient studies associate neural pathological features such as PNI with adverse prognosis in selected cancers, although these associations do not establish causality. In this Mini Review, we summarize the clinical relevance of neural remodeling in cancer, discuss the molecular mechanisms underlying tumor innervation and nerve-tumor communication, and highlight the role of chronic stress in shaping neural regulation of the tumor microenvironment. We further discuss emerging therapeutic strategies targeting stress-related neural signaling, tumor-associated nerves, and neural-immune-tumor interactions. Finally, we propose that understanding cancer neuroscience within a broader stress-brain-immune-tumor framework may provide new opportunities for precision cancer therapy.