Neurogenic inflammation is one component that sculpts the immune milieu of solid tumors. However, it remains unclear how the sensory-neuroimmune axis shapes the immune microenvironment in cold tumors to bolster treatment resistance. Using orthotopic head and neck squamous cell carcinoma (HNSCC) models, we demonstrate that tumor growth-induced sensory hyperexcitability, and surgical sensory signaling interruption reduced tumor growth. Genetic knockout of a key neuropeptide released by sensory neurons, calcitonin gene-related peptide (CGRP), encoded by Calca, produced eradication when paired with multimodal radioimmunotherapy (RT + αPD1). Such treatment reduced Treg infiltration and immunosuppressive function in Calca knockout mice. We also observed that high-dose psilocybin functions as a CGRP inhibitor and transiently reduces tumor growth by increasing antitumor immunity. Additionally, psilocybin increased circulating serotonin, which was partially reversed with platelet activation inhibitor, clopidogrel. We observed differential effects on CD8 and Treg functionality by psilocin in vitro. Correlational analyses in plasma from human subjects following a single-dose psilocybin corroborated these findings. Together, this work underscores the complex interaction of neurogenic inflammation and the tumor immune microenvironment, highlighting potentially new therapeutic avenues for HNSCC and other solid tumors.