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From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review)

  • Authors:
    • Tianxiang Wang
    • Xuemei Zhou
    • Xinhao Yin
    • Axue Zhang
    • Yaxuan Fan
    • Kun Chen
    • Haojun Tao
    • Zhongxin Tang
    • Pingchuan Zhang
    • Xia He
    • Li Yin
  • View Affiliations / Copyright

    Affiliations: Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 76
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    Published online on: August 1, 2025
       https://doi.org/10.3892/ijo.2025.5781
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Abstract

Ferroptosis is an iron‑dependent, lipid peroxidation‑driven form of regulated immunogenic cell death (ICD). ICD has demonstrated potential to overcome resistance to conventional cancer therapies, enhancing the efficacy of treatments such as chemotherapy, radiotherapy, immunotherapy and photodynamic therapy. Notably, in the context of radiotherapy, ferroptosis serves a key role, particularly when combined with radioimmunotherapy. Mitochondria are central to the regulation of radiation‑induced oxidative stress and the remodeling of the immune microenvironment, and they undergo characteristic morphological changes during the ferroptotic process. However, the precise regulatory association between mitochondrial dysfunction and ferroptosis remains incompletely understood, and there is an ongoing debate regarding this complex interaction. The present review aimed to explore the mechanisms through which mitochondria and ferroptosis interact in the context of radiotherapy, with a focus on how ferroptosis exacerbates mitochondrial dysfunction. Additionally, the present review proposed novel strategies leveraging radioimmunotherapy to offer more precise and effective approaches for cancer treatment.
View Figures

Figure 1

Regulatory network of the ferroptosis
defense system. (A) AR/ER-MBOAT1/2: Regulated by ER and AR
signaling, MBOAT1/2 inhibits ferroptosis via phospholipid
remodeling in a GPX4-independent manner. (B) SLC7A11-GSH-GPX4: The
cytoplasmic and mitochondrial GPX4 axis, mediated by GSH, prevents
ferroptosis primarily through the inhibition of PLOOH formation.
(C) DHODH-CoQH2: The electrons generated from DHODH concurrently
reduce CoQ to CoQH2, which in conjunction with mGPX4, effectively
prevents lipid peroxidation and inhibits ferroptosis. (D)
GCH1-BH4-DHFR: BH4 participates in CoQ synthesis and the REDOX
cycle via DHFR, protecting PUFA-PL from oxidative degradation and
consequently preventing RSL3-induced ferroptosis. (E)
NADPH-FSP1-CoQ: Hydrogen provided by NAD(P)H reduces CoQ to its
reduced form CoQH2, which functions as a lipophilic antioxidant to
inhibit lipid peroxidation and thereby prevent ferroptosis. The
figure was created using Figdraw (www.figdraw.com, ID: UITOP08066). ER, estrogen
receptor; AR, androgen receptor; MBOAT, membrane bound
O-acyltransferase; GPX4, glutathione peroxidase 4; SLC7A11, Solute
Carrier Family 7 Member 11; GSH, glutathione; PLOOH, phospholipid
hydroperoxide; DHODH, dihydroorotate dehydrogenase; BH4,
tetrahydrobiopterin; PUFA-PL, polyunsaturated fatty
acid-phospholipid; NADPH; nicotinamide adenine dinucleotide
phosphate.

Figure 2

Ionizing radiation-induced remodeling
of mitochondrial metabolism regulates ferroptosis. IR augments
glucose and glutamine metabolism, consequently elevating ROS
production and inducing mitochondrial oxidative stress. The
upregulation of ACSL4 expression, autophagic degradation of LDs and
PINK1/Parkin-mediated mitophagy result in increased FFA levels,
thereby promoting lipid peroxidation. In immune cells,
mitochondrial metabolism shifts towards fatty acid oxidation, a
critical pathway that contributes to excessive mitochondrial ROS
generation and T-cell exhaustion. The figure was created using
Figdraw (www.figdraw.com; ID: TIAIY1fbaa).
ACSL4, acyl-CoA synthetase long-chain family member 4; LDs, lipid
droplets; FFA, free fatty acid; ROS, reactive oxygen species.

Figure 3

Mitochondrial metabolic reprogramming
modulates anti-tumor immune responses. In the context of ionizing
radiation, the mitochondrial metabolic state of immune cells such
as T cells, NK cells and macrophages within the tumor
microenvironment undergoes alterations. These changes include
shifts between oxidative phosphorylation and glycolysis, the
production and impact of mtROS, and the immune response triggered
by the release of mtDNA; such modifications facilitate tumor immune
evasion. The key role of mitochondrial morphology and function in
modulating immune cell activity and the tumor immune response is
thereby emphasized. The figure was created using Figdraw
(www.figdraw.com; ID: IOSPS4b55e). NK, natural
killer; mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive
oxygen species.

Figure 4

Strategies for
radioimmunosensitization targeting mitochondrial ferroptosis.
Modulating ferroptosis defense mechanisms, including the ATF4 and
PGC1α pathways, as well as regulating mitochondrial Ca2+
levels, represent effective approaches to enhance radiotherapy
efficacy. By targeting immunogenic cell death associated with
ferroptosis through advanced nanotechnologies such as biomimetic
nanoparticles, nMOFs and trimetallic nanoparticles, the synergistic
effects of ferroptosis in radioimmunotherapy can be harnessed to
augment immune responses and overcome tumor immune evasion. The
figure was created using Figdraw (www.figdraw.com; ID: PAWUTb4f45).ATF4, activating
transcription factor 4; nMOFs, nano-metal-organic frameworks.
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Copy and paste a formatted citation
Spandidos Publications style
Wang T, Zhou X, Yin X, Zhang A, Fan Y, Chen K, Tao H, Tang Z, Zhang P, He X, He X, et al: From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review). Int J Oncol 67: 76, 2025.
APA
Wang, T., Zhou, X., Yin, X., Zhang, A., Fan, Y., Chen, K. ... Yin, L. (2025). From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review). International Journal of Oncology, 67, 76. https://doi.org/10.3892/ijo.2025.5781
MLA
Wang, T., Zhou, X., Yin, X., Zhang, A., Fan, Y., Chen, K., Tao, H., Tang, Z., Zhang, P., He, X., Yin, L."From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review)". International Journal of Oncology 67.3 (2025): 76.
Chicago
Wang, T., Zhou, X., Yin, X., Zhang, A., Fan, Y., Chen, K., Tao, H., Tang, Z., Zhang, P., He, X., Yin, L."From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review)". International Journal of Oncology 67, no. 3 (2025): 76. https://doi.org/10.3892/ijo.2025.5781
Copy and paste a formatted citation
x
Spandidos Publications style
Wang T, Zhou X, Yin X, Zhang A, Fan Y, Chen K, Tao H, Tang Z, Zhang P, He X, He X, et al: From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review). Int J Oncol 67: 76, 2025.
APA
Wang, T., Zhou, X., Yin, X., Zhang, A., Fan, Y., Chen, K. ... Yin, L. (2025). From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review). International Journal of Oncology, 67, 76. https://doi.org/10.3892/ijo.2025.5781
MLA
Wang, T., Zhou, X., Yin, X., Zhang, A., Fan, Y., Chen, K., Tao, H., Tang, Z., Zhang, P., He, X., Yin, L."From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review)". International Journal of Oncology 67.3 (2025): 76.
Chicago
Wang, T., Zhou, X., Yin, X., Zhang, A., Fan, Y., Chen, K., Tao, H., Tang, Z., Zhang, P., He, X., Yin, L."From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review)". International Journal of Oncology 67, no. 3 (2025): 76. https://doi.org/10.3892/ijo.2025.5781
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