Tumor Microenvironment Gene Regulation in Oral Squamous Cell Carcinoma: A Systematic Review

Background: The oral squamous cell carcinoma (OSCC) is a very aggressive cancer that is the product of tumor cell interactions with the microenvironment. The tumor microenvironment (TME) has a severe impact on OSCC progression, metastasis, and resistance to treatment by altering gene expression via various cellular and molecular signal transductions. Aim: This review systematizes the information on gene regulation in the OSCC TME (cellular components, signaling pathways that regulate tumor progression and resistance). Methods: We used PRISMA guidelines to search PubMed, Scopus, Web of Science, and Google Scholar (up to April 2025) with OSCC studies addressing the subject of gene regulation and tumor microenvironment. The quality of human or experimental models was evaluated using the Newcastle–Ottawa Scale and the qualitative synthesis was performed because of heterogeneity. Results: The significant regulatory functions of tumor-associated macrophages, cancer-associated fibroblasts, immune cells, and non-coding RNAs were found, especially in the pathways like JAK/STAT, EGFR, Wnt/ -β catenin, and PI3K/AKT/mTOR. Conclusions: The conceptualization of gene regulatory networks in the OSCC TME identifies the emerging biomarkers and targets of therapy. Merging multimodal omics and single-cell studies can further contribute to the precision strategies to enhance the outcomes of OSCC.