{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:37:28Z","timestamp":1793381848610,"version":"4.5.0"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Perineural invasion (PNI) is a distinct route of spread in head and neck cancer and portends recurrence despite optimized surgery\u2013radiotherapy backbones. Emerging cancer\u2212neuroscience and immuno\u2212oncology insights reframe PNI as a neuro\u2212immune niche, in which neurotrophic signaling (GDNF\u2013RET, NGF\u2013TrkA), Schwann\u2212cell plasticity, and neuromodulators (adenosine via CD39\/CD73\u2013A2A; nociceptor\u2212derived CGRP) calibrate tumor behavior and immune tone along cranial nerves. Evidence spanning clinical and experimental models shows matrix\u2212dominated, immune\u2212excluded interfaces; adjuvant radiotherapy and nerve\u2212pathway\u2212directed target design mitigate local risk, while agents (A2A antagonists, TrkA inhibitors, CCR5 blockade) may counter perineural programs. Notably, deployment as immunity enablers remains uncertain, with unresolved issues in PNI quantification, biomarker selection, pharmacodynamic monitoring, and combinations with checkpoint or cellular therapy. In this review, building on cancer\u2212neuroscience frameworks, we synthesize mechanistic drivers of the perineural niche, appraise efficacy\u2212 and safety\u2212oriented pathology\/imaging readouts and drugging opportunities spanning neural and immunometabolic circuits, and outline sequencing with locoregional measures to restore durable immunity. In addition, we discuss how nociceptor signaling and adenosinergic signaling intersect with Schwann\u2212cell programs to regulate the balance between perineural immunosuppression and anti\u2212tumor immunity. The purpose of this article is to define PNI as a neuro\u2212immune niche in head and neck cancer and delineate biomarker\u2212guided therapeutic strategies for clinical testing.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1719675","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T06:29:52Z","timestamp":1765261792000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Perineural invasion as a neuro\u2212immune niche in head and neck cancer: mechanisms of immune evasion and therapeutic implications"],"prefix":"10.3389","volume":"16","author":[{"given":"Simin","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"106420","DOI":"10.1016\/j.oraloncology.2023.106420","article-title":"Adjuvant radiotherapy mitigates impact of perineural invasion on oncologic outcomes in early-stage oral cavity squamous cell carcinoma. 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