Work

Moonlighting function of extracellular GPX4 on immunogenicity of ferroptosis

Year: 2026

Type: article

Abstract: The immunogenic potential of cell death is a key determinant of therapeutic efficacy in cancer. 1 The lytic modalities and the release of damage-associated molecular patterns (DAMPs) derived from dying tumor cells, such as high-mobility group box 1 (HMGB1), could promote dendritic cell (DC) maturation and subsequent T cell priming, which ultimately generates durable and effective antitumor immune responses.Thus, immunogenic cell death not only achieves tumor volume regression, but also functions as an in situ vaccine, activating adaptive immune responses and establishing a long-lasting network of antitumor immune surveillance.The conventional first-line clinical treatments, including chemotherapy, radiotherapy, and chemo-immunotherapy, induce cancer cell death that displays robust immunogenic cell death features, suggesting a major paradigm shift in tumor intervention strategies from purely physical cytotoxicity toward approaches that also incorporate immune remodeling.As a highly promising anticancer strategy, the therapeutic potential of ferroptosis has become a major frontier in the tumor therapy field, especially in the refractory tumors. 2 Ferroptosis, a regulated form of programmed cell death often accompanied by membrane lipid peroxidation, membrane rupture, and the release of intracellular contents, was initially presumed to be strongly immunogenic.3 However, additional evidence has revealed that classical ferroptosis-inducing strategies may also trigger ferroptosis in immune cells within the tumor microenvironment, thereby weakening the immune responses required for effective antitumor responses.4 Several studies have shown that immune cells undergoing ferroptosis secrete suppressive mediators such as PGE2, IDO, and oxidized lipids, which can markedly inhibit the proliferation and cytotoxic activity of CD8 + T cells, thereby promoting immune evasion and therapeutic resistance. 1 , 4 Thus, ferroptosis displays a double-edged role in tumor immunity and the net effect of immunological outcome is dictated by the dynamic balance between immunostimulatory and immunosuppressive signals within the tumor microenvironment.In a recent study published in Cell , 5 Liu et al. provide compelling evidence that ferroptotic cancer cells elicit significantly weaker antitumor immune responses than apoptotic, necroptotic, or cuproptotic cells.This finding further supports the existence of ferroptosis-selective immunosuppres-✩

Source: Journal of the National Cancer Center

DOI: 10.1016/j.jncc.2026.06.005

Authors: Xin Wang, Dongqing Wang, Haitao Zhu

Institutions: Affiliated Hospital of Jiangsu University, Jiangsu University

Language: English

Topic: Ferroptosis and cancer prognosis

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,160