Extracellular landscape of ferroptosis: A new direction to enhance anti-tumor efficacy

Wanxin Guo

1,2,#

Lei Qian

1,2,#

Susu Guo

Shiyu Qiu

Xiangfei Xue

Lifang Ma

1,2,3

Xiao Zhang

Yongchun Yu

2,*

Jiayi Wang

1,2,3,*

Affiliation +

*Correspondence to: Yongchun Yu, Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. E-mail: yyc2166@sjtu.edu.cn
Jiayi Wang, Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Medical Science Laboratory, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. E-mail: Jiayi.wang@sjtu.edu.cn

Ferroptosis Oxid Stress. 2027;3:202629. 10.70401/fos.2026.0047

Received: June 15, 2026Accepted: September 30, 2026Published: September 30, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Ferroptosis is an iron-dependent form of regulated cell death driven by the lethal accumulation of lipid peroxides. Accumulating evidence indicates that the extracellular landscape, the acellular functional subset of the tumor microenvironment (TME) comprising the extracellular matrix, soluble metabolites, cytokines, extracellular vesicles (EVs), and physicochemical conditions such as pH and oxygen content, actively determine cellular susceptibility to ferroptosis. Extracellular nutrients, acidic and hypoxic conditions modulate intracellular redox homeostasis, while ferroptosis-related signals are transmitted between cells through EVs, cytokines, and metabolites. Ferroptosis in turn bidirectionally shapes anti-tumor immunity, acting as immunogenic cell death yet also releasing immunosuppressive mediators that impair T cells. This review summarizes the canonical intracellular mechanisms of ferroptosis, highlights the bidirectional crosstalk between cells and the extracellular landscape, and discusses therapeutic strategies targeting this landscape, including reshaping nutrient availability, engineering EV-based delivery systems, and designing microenvironment-responsive nanomaterials. Key limitations of the field and perspectives are also outlined for safe and effective ferroptosis-based anti-tumor therapies.

Keywords

Ferroptosis, extracellular landscape, tumor microenvironment, anti-tumor immunity

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Guo W, Qian L, Guo S, Qiu S, Xue X, Ma L, et al. Extracellular landscape of ferroptosis: A new direction to enhance anti-tumor efficacy. Ferroptosis Oxid Stress. 2027;3:202629. https://doi.org/10.70401/fos.2026.0047

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Ferroptosis and Oxidative Stress

Extracellular landscape of ferroptosis: A new direction to enhance anti-tumor efficacy

Wanxin Guo

Lei Qian

Susu Guo

Shiyu Qiu

Xiangfei Xue

Lifang Ma

Xiao Zhang

Yongchun Yu

Jiayi Wang

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Ferroptosis and Oxidative Stress

Extracellular landscape of ferroptosis: A new direction to enhance anti-tumor efficacy

Wanxin Guo

Lei Qian

Susu Guo

Shiyu Qiu

Xiangfei Xue

Lifang Ma

Xiao Zhang

Yongchun Yu

Jiayi Wang

Abstract

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