Coupling oxidative de-stabilization with immune activation overcomes radioresistance in hepatocellular carcinoma
7 affiliations
- 1Department of Radiology, Central South University, The Third Xiangya HospitalNo. 138, Tongzipo Road, Changsha, 410013 Hunan China
- 2Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Singapore
- 3Postdoctoral Station of Medical Aspects of Specific Environments, the Third Xiangya Hospital, Central South University, Changsha, China
- 4Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University, and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117 China
- 5Shandong Medical College, No. 5460, Second Ring South Road, Jinan, 250002 Shandong China
- 6Transplantation Center, The Third Xiangya Hospital, Central South University, No. 138, Tongzipo Road, Changsha, 410013 Hunan China
- 7Furong Laboratory, Changsha, 410008 Hunan China
Abstract
Background: Radioresistance in hepatocellular carcinoma (HCC) is a coordinated adaptive state rather than failure of a single pathway, sustained by reinforced redox buffering and suppressed immune activation. Strategies that intensify radiation damage without disrupting this state have shown limited efficacy. We sought to determine whether radiosensitization can be achieved by destabilizing tumor oxidative homeostasis while restoring immune competence.
Methods: A BSA-templated Fe/Mn nanoassembly incorporating the thiol-reactive agent RRX-001 and folate targeting (BFMR-FA) was developed as a multifunctional and MRI-visible platform. Its biological effects were evaluated across radioresistant cellular systems, organoids, and orthotopic tumor models.
Results: BFMR-FA shifts the redox equilibrium of tumor cells beyond a recoverable threshold. By depleting glutathione and suppressing the SLC7A11–GPX4 axis, it converts radiation-induced oxidative stress from a transient signal into sustained lipid peroxidation, resulting in convergent ferroptotic and apoptotic cell death. This transition is accompanied by the emergence of immunogenic stress signals and activation of the STING–TBK1–IRF3 pathway, enabling dendritic cell maturation and expansion of cytotoxic T-cell responses. In vivo, these effects translate into near-complete suppression of radioresistant tumor growth with systemic tolerance. The Fe/Mn composition enables direct visualization of intratumoral delivery by T1-weighted MRI.
Conclusion: These findings support a model in which radiosensitization is achieved not by amplifying tumor damage alone, but by collapsing the adaptive redox state that constrains it. The resulting oxidative destabilization coupled with immune activation defines an oxidative homeostasis collapse–driven radio-immuno synergy, providing a generalizable framework for overcoming therapeutic resistance in solid tumors.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12943-026-02729-z.
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BibTeX
@article{liu2026coupling,
title = {{Coupling oxidative de-stabilization with immune activation overcomes radioresistance in hepatocellular carcinoma}},
author = {Jiahao Liu and Ze Mi and Hongpei Tan and Junhong Duan and Feilong Huang and Shahan Guo and Yuting Li and Jianmin Wu and Min Yang and Yunjie Liao and Xiaoqian Ma and Qi Liang and Weiwei Zhang and Xiaofei Fan and Pengfei Rong},
journal = {Molecular Cancer},
year = {2026},
month = jul,
doi = {10.1186/s12943-026-02729-z},
url = {https://doi.org/10.1186/s12943-026-02729-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Coupling oxidative de-stabilization with immune activation overcomes radioresistance in hepatocellular carcinoma
AU - Jiahao Liu
AU - Ze Mi
AU - Hongpei Tan
AU - Junhong Duan
AU - Feilong Huang
AU - Shahan Guo
AU - Yuting Li
AU - Jianmin Wu
AU - Min Yang
AU - Yunjie Liao
AU - Xiaoqian Ma
AU - Qi Liang
AU - Weiwei Zhang
AU - Xiaofei Fan
AU - Pengfei Rong
PY - 2026
DA - 2026/07/30
JO - Molecular Cancer
DO - 10.1186/s12943-026-02729-z
UR - https://doi.org/10.1186/s12943-026-02729-z
AB - Background: Radioresistance in hepatocellular carcinoma (HCC) is a coordinated adaptive state rather than failure of a single pathway, sustained by reinforced redox buffering and suppressed immune activation. Strategies that intensify radiation damage without disrupting this state have shown limited efficacy. We sought to determine whether radiosensitization can be achieved by destabilizing tumor oxidative homeostasis while restoring immune competence. Methods: A BSA-templated Fe/Mn nanoassembly incorporating the thiol-reactive agent RRX-001 and folate targeting (BFMR-FA) was developed as a multifunctional and MRI-visible platform. Its biological effects were evaluated across radioresistant cellular systems, organoids, and orthotopic tumor models. Results: BFMR-FA shifts the redox equilibrium of tumor cells beyond a recoverable threshold. By depleting glutathione and suppressing the SLC7A11–GPX4 axis, it converts radiation-induced oxidative stress from a transient signal into sustained lipid peroxidation, resulting in convergent ferroptotic and apoptotic cell death. This transition is accompanied by the emergence of immunogenic stress signals and activation of the STING–TBK1–IRF3 pathway, enabling dendritic cell maturation and expansion of cytotoxic T-cell responses. In vivo, these effects translate into near-complete suppression of radioresistant tumor growth with systemic tolerance. The Fe/Mn composition enables direct visualization of intratumoral delivery by T1-weighted MRI. Conclusion: These findings support a model in which radiosensitization is achieved not by amplifying tumor damage alone, but by collapsing the adaptive redox state that constrains it. The resulting oxidative destabilization coupled with immune activation defines an oxidative homeostasis collapse–driven radio-immuno synergy, providing a generalizable framework for overcoming therapeutic resistance in solid tumors. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12943-026-02729-z.
SN - 1476-4598
ER -