Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.

Background and purpose Melkersson‐Rosenthal syndrome (MRS) is a rare neuro‐mucocutaneous disease. In addition to the traditional clinical triad, there is also a diversity of clinical signs, and it may be related to other systemic diseases. Methods In the present study, we report a case of MRS with endocrine disorders that exhibits extraordinary therapeutic efficiency by using hydroxychloroquine (HCQ), explore whether there is an internal connection between MRS and endocrine disorders, and discuss the mechanism of the therapeutic efficiency of using HCQ. The hypothesis proposed for the first time is that MRS may essentially be a systemic granulomatous disease. Results The physical examination revealed orofacial swelling and fissured tongue. The histopathologic examination showed epithelioid granulomas. Combined with the other examination, this case was diagnosed as incomplete MRS. HCQ and local drugs were introduced. The patient achieved clinical recovery and psychological cure by the 18‐week follow‐up, and the 1‐year follow‐up found no reactivation of MRS. Moreover, the levels of cortisol and adrenocorticotropic were within normal ranges. Conclusions After the drug therapy was targeted at granuloma, not only did all of the symptoms related to MRS disappear, but the endocrine system also returned to normal. It is speculated that the endocrine disorder in this patient may be related to MRS. We further propose the first‐time hypothesis that MRS may essentially be a systemic granulomatous disease. It provides a new medication method with high‐level efficiency.