Central nervous system and cancer: mechanistic insights and therapeutic opportunities CNS and cancer: a review.

Cancer is increasingly recognized as a systemic disease whose biology is shaped by reciprocal interactions with its microenvironment, including the central and peripheral nervous systems. Recent evidence demonstrates that neural inputs can directly promote tumour growth through synaptic, paracrine, and neuroendocrine mechanisms, and that these inputs intersect with canonical drug-resistance pathways, creating new opportunities and challenges for precision oncology. Primary brain tumours such as gliomas form bona fide functional synapses with neurons, hijacking both excitatory (AMPA/NMDA) and inhibitory (GABA_A) inputs to sustain proliferation. Comparable mechanisms are now described in brain metastases and, remarkably, in small cell lung cancer (SCLC), where cortical and vagal neurons establish synaptic contacts with tumour cells. Beyond synaptic communication, paracrine neurotransmitter signalling, tumour innervation, autonomic balance (β-adrenergic versus vagal tone), and systemic stress responses jointly modulate tumour biology, immune surveillance, and therapeutic response. Convergent evidence further indicates that neural and stress-related signalling cooperates with classical resistance circuits-including p53-EGFR-ERK signalling, P-glycoprotein-mediated drug efflux, reactive oxygen species (ROS)-dependent redox programmes, and adipokine-Hsp90 axes-to attenuate the efficacy of chemotherapy, targeted agents, and immune checkpoint inhibitors. Neuron-tumour interactions represent a novel and clinically actionable dimension of cancer pathogenesis that extends well beyond gliomas. Targeting neuron-tumour synapses, neurotransmitter pathways, autonomic inputs, and the resistance circuits with which they intersect offers new therapeutic opportunities, but translation requires careful attention to specificity, neurological safety, and rational combination with cytotoxic, targeted, and immune therapies. Cancer is not driven solely by genetic mutations; it is also shaped by signals from the nervous system. This review synthesizes how nerves and brain activity directly influence tumour growth across multiple diseases-including gliomas, small cell lung cancer, breast cancer, pancreatic cancer, and prostate cancer-and how these neural signals converge with metabolic and drug-resistance pathways that limit the efficacy of conventional therapy. Recent discoveries show that some cancers form direct synapse-like connections with neurons and exploit neurotransmitters to fuel tumour progression and treatment escape. Understanding these interactions opens new therapeutic opportunities-such as targeting neural signalling, autonomic pathways, or neuro-modulated resistance mechanisms-and positions the nervous system as a previously underappreciated but clinically relevant driver of cancer behaviour.