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Background: Biological and prognostic roles of programmed death ligand-1 (PD-L1) remain unclear in oral squamous cell carcinoma (OSCC). The controversies role of tumor microenvironmental IFN-γ, pivotal roles in host responses to malignant cells, in oral cancer growth and PD-L1 expression was under-investigated. We examined the mechanism of PD-L1 regulation with focus on interferon gamma in vitro and in clinical samples. Triptolide is the bioactive compound isolated from Tripterygium wilfordii, which has been reported exhibit anti‑inflammatory and antitumor activities. Moreover, we investigated whether TPL affected suppression of PD-L1 is involved in its anti-cancer activity. Methods: The PD-L1 expressions were analyzed by immunohistochemistry in 135 tissues samples. We analysed the production of IFN-γ at oral cancer cell by enzyme-linked immunosorbent assay (ELISA) analysis. IFN-ϒ on oral cancer cell proliferation were examined. We investigated the anticancer of the TPL on human oral cancer by targeted PD-L1 in vitro and patient-derived tumor xenograft (PDTX) models. Findings: PD-L1 overexpression was significant in the tumor site of oral cancer (P < .01). IFN-γ driven the PD-L1 expression oral cancer cells in a dose-dependent manner. The TPL inhibits tumor growth in oral cancer PDTX model with suppressing the PD-L1 expression. The TPL also suppresses the oral cancer cell PD-L1 expression in an interferon-gamma microenvironment. Interpretation: Our results provide evidence for clinical development of PD-L1 targeting therapy in OSCC treatment in future. Funding Statement: This study was supported by research grants from Tri-Service General Hospital, Taiwan, Republic of China (grants Nos. TSGH-C106-004- 006-008-S05, TSGH-C107-008-S06, TSGH-C108-007-008-S06), Ministry of Science and Technology, Taiwan, Republic of China (grants No. MOST 105- 2314-MAB-106-090). Declaration of Interests: All authors have completed the disclosure forms and declare that: no support, financial or otherwise, has been received from any organization that may have an interest in the submitted work; and there are no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: The experiments were conducted according to the ethical guidelines of the institutional review board (TSGH-2-102-05-111) of the National Defense Medical Center, Taiwan.

Biological and prognostic roles of programmed death ligand 1 (PD-L1) remain unclear in oral squamous cell carcinoma (OSCC). Moreover, the pivotal role of tumor microenvironmental interferon-gamma (IFN-γ) in host responses to malignant cells, oral cancer growth, and PD-L1 expression has not been adequately studied. Thus, PD-L1 expression in 130 OSCC samples was analyzed using immunohistochemistry, which was found significantly overexpressed at the tumor site (P