程序性细胞死亡配体-1（PD-L1）是一种抗肿瘤免疫分子，是治疗口腔癌的一个重要靶点。然而，由于多种复杂的途径和肿瘤相关的干扰，其疗效有限。本研究包括150例人类口腔鳞状细胞癌（OSCC）组织样本，其中包括17例相邻正常组织、56例原发肿瘤、47例浸润性肿瘤和30例耐药样本。使用父代/顺铂耐药（CisR-SCC4/9）细胞进行过表达（Jak1-3野生型和催化活性降低型）、沉默（PD-L1 siRNA）、靶向MAPK/PI3K/Jak-Stat通路（SMIs）和检测微粒体。通过RT-PCR、免疫组织化学、Western blot、凝胶酶解分析和MTT分析确定了PD-L1、转录因子（TFs）、信号通路、存活/凋亡、耐药性和侵袭性相关分子及其活性的表达。发现高级OSCC肿瘤（浸润和耐药性）、CisR-SCC4/9细胞和分泌性外泌体（CisR-SCC4/9）中PD-L1表达增加。PD-L1 mRNA/蛋白与不同的TFs（AP1 > Stat3 > c-myc > NFκB）在肿瘤样本中呈正相关。PD-L1表达受Jak-Stat/MAPK-AP1途径的影响优于PI3K。Jak1-3的异位表达提示Jak2诱导的PD-L1水平高于Jak1/Jak3。最后，通过与多种分子的联系，PD-L1直接支持OSCC的存活（Bcl-xL、Bax、剪切的caspase-3）、侵袭（MMP2/9）和耐药性（ALDH-1A1/-3A1）程序。PD-L1主要受Jak2-Stat3/MAPK-AP1途径调控，并且除了常规的免疫功能外，它还支持OSCC的存活、侵袭和耐药性。PD-L1可以作为一个严重程度的指标，并且可以与Jak2-Stat3/MAPK-AP1一起靶向治疗以获得更好的口腔鳞状细胞癌结果。版权所有© 2023 Elsevier B.V. 保留所有权利。

Programmed cell death ligand-1 (PD-L1)is an antitumor immunity molecule and a great target to cure oral cancer; nonetheless, the limited success can be attributed to many complex pathways and tumor-related interferences.In the present study, 150 human oral squamous cell carcinoma (OSCC) tissue samples, including 17 adjacent normals, 56 primary tumors, 47 invasive tumors, and 30 therapy-resistant (RT) samples, were included. The parental/cisplatin-resistant (CisR-SCC4/9) cells were utilized for overexpression (Jak1-3 wild type and catalytically inactive), knockdown (PD-L1 siRNA), targeting MAPK/PI3K/Jak-Stat pathways (SMIs) and checking microsomes. The expression of PD-L1, transcription factors (TFs), signaling pathways, survival/apoptosis, therapy resistance, and invasiveness-related molecules/their activity were determined by RT-PCR, Immunohistochemistry, Western blot, Gelatin Zymography, and MTT assay.Advanced OSCC tumors (invasive and drug-resistance), CisR-SCC4/9 cells, and secretory exosomes (CisR-SCC4/9) were found with increased PD-L1 expression. PD-L1 mRNA/protein showed a positive correlation with different TFs (AP1 > Stat3 > c-myc > NFκB) in tumor samples. The PD-L1 expression was more influenced by Jak-Stat/ MAPK-AP1 pathways over PI3K. The ectopic expression of Jak1-3 suggests Jak2 inducted PD-L1 level over Jak1/Jak3. Finally, PD-L1 directly supports survival (Bcl-xL, Bax, cleaved caspase-3), invasion (MMP2/9), and drug-resistance (ALDH-1A1/-3A1) program in OSCC through its link with several molecules.PD-L1 was regulated mainly by the Jak2-Stat3/ MAPK-AP1 pathway, and besides the routine immunological functions, it supports OSCC survival, invasion, and therapy resistance. PD-L1 can be used as an indicator of severity and can be targeted along with Jak2-Stat3/ MAPK-AP1 for a better outcome OSCC.Copyright © 2023 Elsevier B.V. All rights reserved.