LncRNAs at the frontline of neuroimmune crosstalk in oral cancer

Oral squamous cell carcinoma (OSCC) is one of the most aggressive malignancies, marked by immune evasion and perineural invasion that fuel therapy resistance and poor prognosis. Long non-coding RNAs (lncRNAs) have emerged as key regulators of cancer progression, capable of shaping immune responses and promoting neural invasion. This review examines the developing concept of the nerve-immune-cancer axis, emphasizing new findings on neuroimmune interactions and how lncRNAs influence neuroinflammation. The review summarizes recent studies on the functions of lncRNAs in OSCC, particularly their role in neuroimmune interactions. This review explains how lncRNAs can influence both the immune system and nerve-related signals in OSCC. Unlike previous reviews that address neuronal or immune mechanisms in isolation, this work highlights the convergent neuroimmune pathways potentially regulated by lncRNAs and identifies critical gaps, including the lack of OSCC-specific functional studies, absence of spatial or single-cell resolution of lncRNA activity, and limited in vivo models assessing lncRNA-driven perineural invasion. By articulating these research gaps, this review outlines testable hypotheses regarding lncRNA-mediated regulation of neuroimmune crosstalk and proposes future directions such as functional genomics, spatial transcriptomics, and nerve-tumor co-culture models. Clarifying these mechanisms may enable the identification of novel biomarkers and therapeutic targets, ultimately improving the management of OSCC.