TY  - EJOU
AU  - Li, Ju 
AU  - Rao, Pengcheng 
AU  - Yang, Dan 
AU  - Zhou, Tong 
AU  - Gan, Jianguo 
AU  - Lv, Die 
AU  - Zhou, Shuting 
AU  - Peng, Yang 
AU  - Xia, oqiang 
AU  - Chen, Qianming 
AU  - Jiang, Yuchen 
AU  - Jiang, Jian 
AU  - Xu, Xiaoping 
AU  - Feng, Xiaodong 

TI  - Synergistic Cell Death: Cisplatin Inflames Tumors by Coordinating Multiple Death Programs
T2  - BIOCELL

PY  - 
VL  - 
IS  - 
SN  - 1667-5746

AB  - <b>Objective:</b> 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. <b>Methods:</b> We employed integrated <i>in vitro</i> and <i>in vivo</i> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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.
KW  - Cisplatin; programmed cell death; pyroptosis; necroptosis; ferroptosis; apoptosis

DO  - 10.32604/biocell.2026.075437