Perineural invasion: A neuroimmune axis mediating immunotherapy resistance across malignancies

Perineural invasion has traditionally been regarded as a distinct anatomical route of tumor spread, following direct invasion, hematogenous dissemination, and lymphatic metastasis. However, accumulating evidence indicates that perineural invasion represents more than a passive conduit for cancer dissemination. Perineural invasion is frequently observed in aggressive malignancies, including head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, gastric cancer, melanoma, prostate cancer and breast cancer, and is strongly associated with tumor progression, immune evasion, therapeutic resistance, and poor clinical outcomes. Although immune checkpoint blockade targeting the PD-1/PD-L1 axis has achieved substantial clinical success across multiple cancer types, resistance to immunotherapy remains a major unresolved challenge. Recent studies reveal that perineural invasion and cancer-induced nerve injury actively reshape the tumor immune microenvironment through sustained neuro-immune crosstalk, thereby promoting immune suppression, T-cell dysfunction, and resistance to immunotherapy. Notably, emerging mechanistic insights from pancreatic ductal adenocarcinoma and cutaneous squamous cell carcinoma have provided key evidence supporting the role of PNI-driven neuro-immune interactions in shaping immunotherapy resistance. In this review, we synthesize current evidence delineating the molecular and cellular mechanisms underlying PNI-driven immune remodeling, with a particular focus on neurotrophic signaling, chemokine-mediated immune exclusion, exosome-dependent communication, and chronic neuroinflammatory responses. By redefining perineural invasion as a dynamic neuro-immune regulatory axis, this review provides a conceptual framework for understanding PNI-associated immune escape and highlights emerging therapeutic strategies aimed at overcoming immunotherapy resistance.