Synergistic Cell Death:Cisplatin Inflames Tumors by Coordinating Multiple Death ProgramsOA
Objective:Multiple programmed cell death(PCD)pathways have been individually reported to be triggered by cisplatin,but whether and how they are co-regulated remains unclear.In this study,we comprehensively investigate the spectrum of cisplatin-induced PCD.Methods:We employed integrated in vitro and in vivo models including human cancer cell lines,a Cal27 xenograft mouse model,and paired clinical specimens from an oral squamous cell carcinoma patient receiving neoadjuvant cisplatin-based chemotherapy.A comprehensive methodological suite-encompassing cell death assays,Western blotting,Hematoxylin and eosin staining,immunofluorescence,Cyclic multiplexed tissue staining,and pathway-specific pharmacological inhibitors was utilized to dissect the activation of apoptosis,necroptosis,pyroptosis,and ferroptosis.Results:Cisplatin simultaneously upregulates markers of PCD pathways(including apoptosis,necroptosis,pyroptosis,and ferroptosis)in a dose-or time-dependent manner.Pharmacological inhibition or genetic knockdown of key genes in each pathway significantly reduced cytotoxicity.confirming their functional roles.Notably,indicators of key pro-inflammatory death modalities,pyroptosis and ferroptosis,were prominently co-upregulated in both xenograft tumors and clinical patient samples,suggesting that these two forms of PCD may represent the predominant death forms in cisplatin-induced tumor cell death.Conclusion:Cisplatin induces the coordinated activation of multiple cell death programs within a unified framework.Prominent engagement of immunogenic cell death pathways,particularly pyroptosis and ferroptosis,provides a mechanistic basis for the clinically observed synergy between cisplatin and immune checkpoint blockade therapy.
Ju Li;Pengcheng Rao;Dan Yang;Tong Zhou;Jianguo Gan;Die Lv;Shuting Zhou;Yang Peng;Xiaoqiang Xia;Qianming Chen;Yuchen Jiang;Jian Jiang;Xiaoping Xu;Xiaodong Feng
State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaDepartment of Head and Neck Surgery,Sichuan Cancer Hospital and Institute,Sichuan Cancer Center,School of Medicine,University of Electronic Science and Technology of China,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Frontier Innovation Center for Dental Medicine Plus&Research Unit of Oral Carcinogenesis and Management&Chinese Academy of Medical Sciences,West China Hospital of Stomatology,Sichuan University,Chengdu,China
医药卫生
Cisplatinprogrammed cell deathpyroptosisnecroptosisferroptosisapoptosis
《BIOCELL》 2026 (5)
P.176-196,21
supported by the grants of the National Natural Science Foundations of China(NSFCGrant Nos.82170971,82373187,82273165)the Sichuan Science and Technology Program(Grant Nos.2025NSFJQ0062 and 2024YFFK0293)the Scientific Research Foundation of the West China Hospital of Stomatology,Sichuan University(RD-03-202110)the Special Funding for the State Key Laboratory of Oral Diseases,Sichuan University(SKLOD-2025KP009).
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