Ferroptosis-driven radio-immunosensitization: an emerging mechanistic framework for enhancing response to immune checkpoint inhibitor therapy
- 1Department of Tumor Biological Therapy, Affiliated Cancer Hospital of Inner Mongolia Medical University , ,
Abstract
Immune checkpoint inhibitors (ICIs) provide durable tumor control in some patients, but resistance can develop through tumor-intrinsic and microenvironmental mechanisms. This narrative review examines the metabolic and immune conditions under which ferroptosis may enhance ICI responsiveness or resensitize selected ICI-refractory tumors. Radiotherapy (RT) increases oxidizable phospholipids and can repress SLC7A11, the light-chain component of system xc ⁻ . ICI-activated CD8 ⁺ T cells provide convergent interferon-γ signaling. Tumors can resist this pressure through GPX4, FSP1-CoQ10, mitochondrial DHODH, NRF2-dependent programs, and iron-export pathways. Recent preclinical studies have tested RT with ferroptosis-directed interventions and ICIs. These studies include functional evidence of ferroptosis dependence in radioresistant lung cancer and resensitization of LKB1-deficient, primarily ICI-refractory tumors. The findings support a preclinical rationale for combination therapy, although their causal strength varies. Reversal of clinically defined acquired ICI resistance remains unestablished, and the clinical RT-ICI studies reviewed here did not measure ferroptosis in patients. The immune effects also vary by cell type. Tumor-cell ferroptosis may support immunity, whereas lipid peroxidation in CD8 ⁺ T cells, dendritic cells, or polymorphonuclear myeloid-derived suppressor cells can impair antitumor responses. Translation will require functional validation, cell-resolved biomarkers, achievable drug exposures, and evaluation of RT dose, fractionation, and sequence alongside normal-tissue and immune-cell safety.
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BibTeX
@article{cao2026ferroptosisdriven,
title = {{Ferroptosis-driven radio-immunosensitization: an emerging mechanistic framework for enhancing response to immune checkpoint inhibitor therapy}},
author = {Zhenghao Cao and Xudong Ao},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1954104},
url = {https://europepmc.org/article/PMC/PMC13688023},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ferroptosis-driven radio-immunosensitization: an emerging mechanistic framework for enhancing response to immune checkpoint inhibitor therapy
AU - Zhenghao Cao
AU - Xudong Ao
PY - 2026
DA - 2026/10/08
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1954104
UR - https://europepmc.org/article/PMC/PMC13688023
AB - Immune checkpoint inhibitors (ICIs) provide durable tumor control in some patients, but resistance can develop through tumor-intrinsic and microenvironmental mechanisms. This narrative review examines the metabolic and immune conditions under which ferroptosis may enhance ICI responsiveness or resensitize selected ICI-refractory tumors. Radiotherapy (RT) increases oxidizable phospholipids and can repress SLC7A11, the light-chain component of system xc ⁻ . ICI-activated CD8 ⁺ T cells provide convergent interferon-γ signaling. Tumors can resist this pressure through GPX4, FSP1-CoQ10, mitochondrial DHODH, NRF2-dependent programs, and iron-export pathways. Recent preclinical studies have tested RT with ferroptosis-directed interventions and ICIs. These studies include functional evidence of ferroptosis dependence in radioresistant lung cancer and resensitization of LKB1-deficient, primarily ICI-refractory tumors. The findings support a preclinical rationale for combination therapy, although their causal strength varies. Reversal of clinically defined acquired ICI resistance remains unestablished, and the clinical RT-ICI studies reviewed here did not measure ferroptosis in patients. The immune effects also vary by cell type. Tumor-cell ferroptosis may support immunity, whereas lipid peroxidation in CD8 ⁺ T cells, dendritic cells, or polymorphonuclear myeloid-derived suppressor cells can impair antitumor responses. Translation will require functional validation, cell-resolved biomarkers, achievable drug exposures, and evaluation of RT dose, fractionation, and sequence alongside normal-tissue and immune-cell safety.
SN - 2234-943X
ER -