Cancer Neuroscience: From Local Neuro-Immune Microenvironments to Systemic Brain-Body Circuitry

Classic oncological models have largely restricted cancer pathogenesis to autonomous genetic mutations within localized cells. Current research, however, reframes solid tumors as structurally integrated "pseudo-organs" that rely on host neural networks for survival. This review examines the reciprocal signaling networks connecting nervous, immune, and malignant cells within the tumor microenvironment. At the tissue level, we outline how tumors construct de novo neural architecture via axonogenesis, cellular plasticity, and the assembly of functional neuro-neoplastic synapses. Expanding beyond the local niche, we describe the systemic brain-body circuitry. We specifically address how central nervous system pathways respond to tumor-derived cues and how chronic stress signaling disrupts physiological homeostasis. To explain the associated immune evasion, we analyze how sensory neuropeptides, particularly CGRP and, more broadly, Substance P-NK1R signaling, contribute to immune dysfunction, tumor-promoting inflammation, and therapeutic resistance. Finally, we discuss the clinical implications of these pathways. Rather than relying on nonspecific structural denervation, future therapeutic strategies should focus on targeted "neural reprogramming" to uncouple tumors from their neural dependencies and restore antitumor immunity while minimizing neurotoxicity. Ultimately, this review conceptualizes solid tumors as systemically integrated entities, establishing a framework for precision neural reprogramming to overcome immune evasion and therapeutic resistance.