Sensory innervation shapes cancer immunotherapy efficacy and adverse events.

Sensory neurons innervate the tumor microenvironment (TME) and are active contributors to tumor progression and immune evasion. Across multiple cancer types, higher intratumoral nerve density is associated with worse clinical outcomes, including increased lymph node metastasis, local recurrence, and reduced survival. This relationship is driven, at least in part, by local immunosuppression arising from neuropeptide and neurotransmitter paracrine signaling within the TME. Nociceptive sensory neurotransmission impacts tumor-infiltrating immune cells to promote T-cell exhaustion, mast cell degranulation, and stromal remodeling, collectively constructing a barrier to effective antitumor immunity. Beyond paracrine signaling, sensory neurons themselves express immune checkpoint proteins, including programmed cell death ligand-1, providing an additional mechanism by which the sensory nervous system participates in local immune regulation. Preclinical studies have established that targeting sensory neuron signaling, whether through denervation, neuropeptide antagonism, or axon guidance inhibition, can relieve TME immunosuppression and improve the efficacy of immune-based therapies. Several Food and Drug Administration (FDA)-approved agents developed for non-oncologic indications, including calcitonin gene-related peptide receptor antagonists approved for migraine, and the NK-1R antagonist Aprepitant, represent immediately available candidates for repurposing in combination immunotherapy strategies. The relationship between sensory neurons and immunotherapy is bidirectional; however, immunotherapies also act on sensory neurons, and this interaction likely contributes to the development and severity of immune-related adverse events through disruption of constitutive neuronal checkpoint signaling and neurogenic amplification of tissue inflammation. Sensory neurons in densely innervated barrier organs may serve as neuroimmune amplifiers that worsen the severity of colitis, pneumonitis, and dermatitis during checkpoint blockade. This review examines the evidence for how sensory neural signaling shapes immunotherapy efficacy, and how immunotherapies impinge on sensory neuron biology to promote adverse events. Throughout, we highlight translational opportunities where modulation of the sensory nervous system may improve therapeutic outcomes or reduce treatment toxicity.