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

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.

Keywords: ferroptosis; mitochondrial dysregulation; radioimmunotherapy.

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.