She Han, Li Tian-Ran, Zhao Guozhi, Yi Liang, Liu Qing, Liu Zheng-Chao, Pei Hao-Yu, Li Xunjia, Zuo Deyu, Mao Qingxiang, Li Yong
Department of Anesthesiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China.
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China.
Cancer Lett. 2025 Aug 10;625:217805. doi: 10.1016/j.canlet.2025.217805. Epub 2025 May 19.
Glioblastoma (GBM), Isocitrate Dehydrogenase-wildtype (IDH-WT) represents the most prevalent and clinically aggressive subtype of adult diffuse gliomas, typically associated with poor prognosis. Temozolomide (TMZ) remains the first-line chemotherapeutic agent for GBM; however, the emergence of TMZ resistance represents a major therapeutic obstacle in clinical practice. This study identifies placenta-specific 8 (PLAC8) as a novel mediator of TMZ resistance in IDH-WT GBM. Elevated PLAC8 expression was strongly correlated with poorer survival rates, higher tumor grades in glioma, establishing it as an independent prognostic factor. Notably, consistent upregulation of PLAC8 was observed in both TMZ-resistant GBM cells and TMZ-treated patients, suggesting its potential as a biomarker for TMZ resistance. Mechanistic studies revealed that PLAC8 regulates TMZ sensitivity in GBM cells through the AKT-mTOR signaling pathway. Additionally, integrated bioinformatics and clinical analyses demonstrated that PLAC8 expression positively correlates with immune cell infiltration while promoting an immunosuppressive tumor microenvironment and modulating immunotherapy-related biomarkers, suggesting its potential as a predictive biomarker for immunotherapy response. In conclusion, PLAC8 represents a promising biomarker and therapeutic target for overcoming TMZ resistance and guiding immunotherapy in GBM. This study provides valuable insights for the development of personalized treatment strategies aimed at improving patient outcomes.
胶质母细胞瘤（GBM），异柠檬酸脱氢酶野生型（IDH-WT）是成人弥漫性胶质瘤中最常见且临床侵袭性最强的亚型，通常预后较差。替莫唑胺（TMZ）仍然是GBM的一线化疗药物；然而，TMZ耐药的出现是临床实践中的主要治疗障碍。本研究确定胎盘特异性8（PLAC8）是IDH-WT GBM中TMZ耐药的一种新型介质。PLAC8表达升高与较差的生存率、胶质瘤中较高的肿瘤分级密切相关，使其成为一个独立的预后因素。值得注意的是，在TMZ耐药的GBM细胞和接受TMZ治疗的患者中均观察到PLAC8持续上调，表明其作为TMZ耐药生物标志物的潜力。机制研究表明，PLAC8通过AKT-mTOR信号通路调节GBM细胞对TMZ的敏感性。此外，综合生物信息学和临床分析表明，PLAC8表达与免疫细胞浸润呈正相关，同时促进免疫抑制性肿瘤微环境并调节免疫治疗相关生物标志物，表明其作为免疫治疗反应预测生物标志物的潜力。总之，PLAC8是克服GBM中TMZ耐药和指导免疫治疗的一个有前景的生物标志物和治疗靶点。本研究为制定旨在改善患者预后的个性化治疗策略提供了有价值的见解。
