Research Progress on the Regulation of Immune Microenvironment by Internal and External Factors in Oral Squamous Cell Carcinoma (OSCC)

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most prevalent malignant tumors globally, and its prognosis is severely constrained by chemotherapy resistance. Existing treatment methods often face bottlenecks due to selective toxicity and recurrent resistance. In recent years, combination chemotherapy and targeted therapy have become important strategies to overcome resistance by regulating the tumor immune microenvironment (TME). Research has revealed multidimensional resistance mechanisms, including abnormal signaling pathways, non-coding RNA regulation, and TME remodeling. This article systematically analyzes the intrinsic and extrinsic regulatory factors of cisplatin resistance in OSCC: On the intrinsic level, CMTM6 activates the Wnt pathway through the ENO-1/AKT/GSK3β axis, HPRT1 upregulates the MMP1/PI3K/Akt pathway, and the imbalance of the GAS5/miR-196a axis drives resistance; on the extrinsic level, circ-ILF2 induces M2 polarization of macrophages and the secretion of pro-drug resistance factors by CAFs, thereby remodeling the TME. The study suggests that targeting PD-L1, the PI3K/AKT pathway, or combining immune checkpoint inhibitors can significantly reverse resistance. These results provide a molecular basis for optimizing OSCC treatment strategies, with molecules such as CMTM6 and circ-ILF2 serving as potential biomarkers or therapeutic targets. Future research should focus on large-scale clinical trials to validate the efficacy of combination therapies, integrate single-cell sequencing with spatial omics to analyze dynamic changes in the TME, and explore emerging mechanisms such as metabolic reprogramming to promote personalized treatment and improve patient outcomes.