Neuro-tumoral dialogue: A comprehensive review of molecular mechanisms, clinical heterogeneity, and therapeutic frontiers

Cancer neuroscience has fundamentally redefined malignancy, repositioning the nervous system from a passive structural element to an integral driver of tumor progression. This review provides a systematic examination of the dynamic, bidirectional dialogue between neurons and cancer cells, dissecting its molecular foundations, context-dependent heterogeneity, and emerging therapeutic vulnerabilities. We detail how tumors exploit the nervous system’s signaling architecture co-opting neurotransmitters, neurotrophins, and developmental axon guidance programs to promote their proliferation and dissemination. A central thesis of this work is the crucial mechanistic divergence between malignancies: central nervous system tumors establish functional synaptic integration with neural circuits, whereas peripheral cancers like pancreatic and prostate are characterized by a complex interplay between autonomic (sympathetic and parasympathetic) remodeling and sensory nerve activation, including aggressive perineural invasion. Furthermore, we explore the critical neuroimmune crosstalk, through which neural signals orchestrate an immunosuppressive tumor microenvironment and thereby undermine the efficacy of immune checkpoint blockade. This evolving understanding unlocks a new class of oncologic strategies, including pharmacological receptor blockade, denervation, and combination therapies designed to resensitize tumors to immunotherapy. However, significant barriers, particularly inter-tumoral heterogeneity and the limitations of current preclinical models, challenge the path to clinical application. Advancing this frontier will necessitate the establishment of validated neural biomarkers, the development of sophisticated patient-derived co-culture systems, and the application of spatial multi-omics to translate the foundational principles of cancer neurobiology into a new generation of effective cancer treatments.