Oral squamous cell carcinoma (OSCC) represents the most common type of head and neck squamous cell carcinoma (HNSCC), which arises from the mucosal epithelium of the oral cavity and impairs appearance, pronunciation, swallowing, and flavor perception (Jagadeesan et al., 2024, Tan et al., 2023). OSCC still has a poor prognosis and high mortality owing to the limited therapeutic efficacy of conventional treatments (Li et al., 2024). The development of immunotherapy has revolutionized the treatment of OSCC; however, this therapy is only successful for a small fraction of OSCC patients due to the heterogeneity (He et al., 2025). Immune evasion has been shown to play a critical role in the low efficacy of immunotherapy in HNSCC (Seliger et al., 2020). Altered energy metabolism is a hallmark of cancers, which is featured by preferential dependence on glycolysis (also known as the Warburg effect) for energy production and cancer cell survival in an oxygen-independent manner (Chelakkot et al., 2023). Notably, the acidification of the tumor microenvironment (TME) triggered by lactate production is recognized to promote immune evasion (Chen et al., 2022). Therefore, researching mechanisms underlying glycolysis and immune evasion in OSCC assumes paramount importance, which may reveal targets and offer novel strategies for OSCC immunotherapy.

DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is at the center of mTORC1 and mTORC2 complexes and inhibits the kinase activity of mTOR, which participates in cell growth, autophagy, and endoplasmic reticulum stress responses (Catena & Fanciulli, 2017). DEPTOR defects are linked to the development of various cancers (Caron et al., 2018). For instance, DEPTOR functions as a tumor suppressor that depresses lymphomagenesis (Xiong et al., 2025). DEPTOR upregulation dampens lung tumorigenesis by blocking mTOR signaling (Gong et al., 2021). Ectopic DEPTOR hinders the proliferation of gastric cancer cells by disrupting the mTOR pathway (Ma et al., 2023). mTOR has been documented to drive glycolysis in carcinogenesis (Fan et al., 2021). Additionally, the activation of the mTOR pathway is implicated in the immune evasion of many cancers (Kobayashi et al., 2020). Whether DEPTOR represses glycolysis and immune escape in OSCC by regulating mTOR signaling is unclear.

Our bioinformatics analysis predicted that nuclear factor 1/C (NFIC) might be a transcription factor regulating DEPTOR that is also differentially expressed in OSCC. NFI is a family of transcription factors (NFIA, NFIB, NFIC, and NFIX) that perform essential roles in normal development and orchestrate cell proliferation and differentiation by transcriptionally controlling their target genes (Chen et al., 2017). The tumor-repressing impact of NFIC has been demonstrated in numerous cancers. For example, NFIC is poorly expressed in non-small cell lung cancer (NSCLC) tissues and cells, and ectopic NFIC impedes the malignant phenotype of NSCLC cells (Shi et al., 2024). Overexpressing NFIC impedes endoplasmic reticulum stress in pancreatic acinar cells and constrains the initiation of pancreatic ductal adenocarcinoma (Cobo et al., 2023). Based on these observations, we speculated that NFIC might control the progression of OSCC via the DEPTOR/mTOR axis. Herein, this study probed the impact of NFIC and DEPTOR on glycolysis and immune evasion in OSCC by modulating the mTOR pathway.