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Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). We investigate how nerves within the tumor microenvironment impact the adaptive immune system and tumor growth. RNA sequencing and proteomics data led us to identify cholinergic nerves as the potential drivers of tumor growth in human and mouse HNSCC. Using three syngeneic orthotopic murine models of HPV-unrelated HNSCC, experimental and pharmacologic manipulation of cholinergic output, and knockout mouse models, we discovered that activation of cholinergic nerves accelerate tumor growth by directly acting on the adaptive immune system. Cholinergic nerve release of calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking cholinergic nerves pharmacologically or genetically increased CD8 T cell activity in vivo. These data support therapeutic translation of cholinergic nerve targeting of CGRP release to enhance antitumor immune response within the HNSCC TME. Citation Format: Laurel B. Darragh, Tiffany T. Pham, Michael M. Knitz, Alexander Nguyen, Laith A. Mukdad, Yazeed Alhiyari, Maie St. John, Sana D. Karam. Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1834.