Perineural invasion in head and neck squamous cell carcinoma: Neuro-immune mechanisms driving immunotherapy resistance and emerging therapeutic strategies.

Perineural invasion (PNI) is a frequent pathological feature of head and neck squamous cell carcinoma (HNSCC) and is increasingly recognized as more than a passive route of tumor dissemination. Emerging clinical and translational evidence suggests that PNI marks a specialized perineural microenvironment that may contribute to reduced sensitivity to immune checkpoint inhibitors (ICIs). Within this niche, tumor-nerve interactions initiate coordinated neural, immune, metabolic, and spatial adaptations that collectively constrain antitumor immunity. Sympathetic and sensory nerves release neurotransmitters and neuropeptides, including norepinephrine and calcitonin gene-related peptide, which induce CD8⁺ T-cell exhaustion, suppress natural killer cell function, and promote immunosuppressive myeloid polarization. Concurrently, neurotrophic signaling enhances epithelial-mesenchymal transition, invasive behavior, and immune evasion, while activation of the CD39/CD73-adenosine-A2A axis reinforces metabolic immunosuppression. These processes are further stabilized by structural and pharmacokinetic barriers within the perineural niche, limiting effective immune and drug access. Clinically, accumulating retrospective and translational evidence suggests that PNI is associated with inferior response rates and survival outcomes following immune checkpoint blockade, although prospective PNI-stratified validation remains limited. Advances in spatial omics, computational pathology, and imaging now enable quantitative characterization of PNI burden and functional states, supporting its potential role as a predictive biomarker. Mechanistically informed therapeutic strategies-including β-adrenergic blockade, CGRP pathway inhibition, adenosine axis targeting, and localized drug delivery systems-offer promising avenues to reprogram this resistant niche. Collectively, this review examines how PNI may define a microenvironment-associated resistance phenotype in HNSCC, while explicitly distinguishing HNSCC-specific evidence from cross-tumor extrapolation and in vitro observations, and we discuss emerging therapeutic strategies for targeting this resistant niche.