Open Access

ARTICLE

Synergistic Cell Death: Cisplatin Inflames Tumors by Coordinating Multiple Death Programs

Ju Li¹, Pengcheng Rao¹, Dan Yang¹, Tong Zhou¹, Jianguo Gan¹, Die Lv¹, Shuting Zhou¹, Yang Peng¹, Xiaoqiang Xia¹, Qianming Chen¹, Yuchen Jiang¹, Jian Jiang², Xiaoping Xu^1,*, Xiaodong Feng^1,*

1 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, China
2 Department 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, China

* Corresponding Authors: Xiaoping Xu. Email: ; Xiaodong Feng. Email:

BIOCELL 2026, 50(5), 7 https://doi.org/10.32604/biocell.2026.075437

Received 31 October 2025; Accepted 27 January 2026; Issue published 13 May 2026

Abstract

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.

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Keywords

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Supplementary Material

Supplementary Material File

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