Perineural invasion in digestive tract tumors: Immune system interactions and therapeutic strategies

Digestive tract tumors represent a substantial global public health challenge, accounting for elevated morbidity and mortality rates. Perineural invasion (PNI), the spread of tumor cells along nerve fibers, has emerged as a key driver of aggressiveness and a poor prognosis. This study systematically reviews the complex, underexplored interplay between PNI and antitumor immunity in gastrointestinal cancers. By analyzing immune-related components (the programmed cell death protein 1/programmed death ligand 1 axis, T cell subsets, tumor-associated macrophages, and other immune checkpoints), it reveals PNI disrupts immune balance: It suppresses T-cell activity via programmed death ligand 1/programmed cell death protein 1 binding, skews T-cell differentiation to reduce antitumor efficacy and boost immunosuppression, and polarizes macrophages to aid tumor progression. These findings provide novel insights into how PNI reshapes the tumor immune microenvironment and promotes metastatic behavior, establishing a framework for prioritizing immunotherapeutic targets to inform precision treatment strategies.