Title : The pre-invasive neural niche: A systematic review of distance-dependent transcriptomic injury in oral squamous cell carcinoma

Background: Perineural invasion (PNI) is a well-established adverse prognostic feature of oral squamous cell carcinoma (OSCC). Traditionally regarded as a late histopathological event, emerging evidence from spatial transcriptomics and single-cell sequencing suggests that neural tissues undergo molecular reprogramming before direct tumor infiltration. These early, distance-dependent transcriptomic alterations may establish a biologically active "pre-invasive neural niche" that facilitates subsequent tumor–nerve interactions. However, this emerging concept has not been systematically synthesized.

Objective: To systematically review and synthesize evidence describing distance-dependent transcriptomic alterations in neural and perineural tissues associated with pre-invasive and early invasive oral squamous cell carcinoma.

Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed, Embase, Scopus, Web of Science, and preprint repositories were searched from inception through December 2025. Human studies involving OSCC or oral potentially malignant disorders, together with relevant experimental models reporting spatially resolved transcriptomic analyses of neural tissues, were included. Data extraction focused on study characteristics, spatial technologies, neural cell populations, distance metrics, and transcriptomic injury signatures. Owing to methodological heterogeneity, findings were synthesized qualitatively.

Results: Fourteen studies met the eligibility criteria. Across spatial transcriptomics, single-cell RNA sequencing, and laser-capture microdissection studies, tumor-proximal neural tissues consistently demonstrated activation of Schwann-cell repair programs, neuroinflammatory signaling, axonal remodeling pathways, and neural injury-response genes. Several investigations reported these molecular alterations before histopathological evidence of perineural invasion, while others demonstrated spatial expression gradients associated with increasing proximity to tumor tissue. Collectively, these findings support the existence of a biologically active pre-invasive neural niche characterized by progressive neural remodeling before overt tumor infiltration.

Conclusions: Current evidence supports the presence of a biologically active, distance-dependent neural niche preceding conventional perineural invasion in OSCC. Recognition of this pre-invasive neural niche provides new insights into neuro–tumor crosstalk and may improve early risk stratification, biomarker discovery, and the development of therapeutic strategies targeting neural remodeling before irreversible nerve invasion occurs.

Atul Kumar Sharma is an MBBS Intern at the All India Institute of Medical Sciences (AIIMS), Nagpur, India, with research interests in cancer biology, translational oncology, and evidence synthesis. He has completed ICMR Short-Term Studentship (STS) projects and multiple systematic reviews, including work in oral cancer. He has undertaken research internships at the Indian Institute of Science (IISc), Bengaluru, in mathematical oncology and at CSIR–Centre for Cellular and Molecular Biology (CCMB), Hyderabad, where he received training in molecular biology and translational cancer research techniques. He aspires to build a career as a physician-scientist dedicated to advancing cancer research and precision oncology.