The neuro-immune oncology axis

Cancer was long viewed primarily as a genetic disease of uncontrolled cellular proliferation. However, emerging evidence highlights the crucial influence of the tumor microenvironment, particularly the interplay between the nervous and immune systems, in driving cancer progression. Recent discoveries, notably the migration of neural progenitor cells from the central nervous system (CNS) to peripheral tumors, introduce a paradigm wherein neural stem cells actively contribute to tumor initiation and progression. In this framework, CNS-derived neural progenitors infiltrate developing tumors, establish new neural networks, and engage in bidirectional communication with immune cells via neuronal signaling molecules (neurotransmitters, neuropeptides, and even ion channels such as ORAI3 and TRPV1). Here we review the detailed molecular and cellular mechanisms underlying this neuro-immune axis in cancer, emphasizing how neurotransmitter signaling, neuropeptide release, and specialized ion channels mediate cross-talk between nerves, immune cells, and malignant cells. We examine these interactions in the context of specific cancers prostate, breast, lung, and pancreatic to illustrate how neural inputs shape immune evasion and tumor progression in each setting. The clinical relevance of neuro-immune crosstalk is discussed, including evidence that tumor innervation correlates with prognosis and can modulate responses to therapy. Finally, we outline emerging therapeutic strategies targeting neural–immune interactions, such as neuromodulatory drugs and nerve-stimulation interventions, which hold promise for enhancing antitumor immunity. By synthesizing these recent insights, we propose a novel view of cancer as a disease of disrupted neuro-immune communication and highlight opportunities to exploit this axis for improved cancer treatment. • Brain-derived DCX + progenitors seed intratumoral nerves that accelerate cancer • β-adrenergic stress suppresses antitumor immunity; vagal ACh can reinvigorate it • Sensory neuropeptides (Substance P, CGRP) drive myeloid skewing and immune evasion • ORAI3/TRPV1 channels link neural signals to tumor growth and immune control • Neural tone predicts prognosis and ICI response; targets include β-blockers, VNS