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REVIEW ARTICLE

Harnessing yttrium-90 selective internal radiation therapy for primary hepatocellular carcinoma: Mechanisms of action and combination strategies

Yue Chai1 ,  Danyang Xu2 ,  Yang Zha3 ,  Pinchao Fan4*
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1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu, China
2 Department of Chemistry, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
3 Breast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
4 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
ARNM 2025, 3(4), 22–37; https://doi.org/10.36922/ARNM025290037
Received: 20 July 2025 | Revised: 12 October 2025 | Accepted: 24 October 2025 | Published online: 17 December 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Yttrium-90 selective internal radiation therapy (90Y-SIRT) has emerged as a transformative locoregional modality for primary hepatocellular carcinoma (HCC) with distinct radiobiological advantages and favorable safety profiles. 90Y-SIRT is expected to break through the limitations of conventional treatment by combining it with other systemic therapies in the treatment of liver cancer at all stages. This review systematically examines: (i) The four mechanistic foundations of SIRT’s therapeutic efficacy, including precise arterial delivery of microspheres, sustained low-dose-rate β-irradiation, tumor-selective high-dose escalation, and modulation of the tumor immune microenvironment; (ii) clinical evidence supporting its dual role in downstaging advanced HCC with portal vein tumor thrombus and enhancing systemic therapy efficacy in intermediate-stage disease; and (iii) comparative studies demonstrating its superiority over transarterial chemoembolization in terms of tumor response, resectability or transplant conversion, and treatment tolerability. In addition, we discuss emerging directions, including the development of cost-effective domestically manufactured microspheres and the integration of biomarker-guided combination regimens to potentiate immunogenic synergy. By integrating mechanistic insights with clinical validation, this review positions 90Y-SIRT as a central pillar in the evolving landscape of precision medicine for primary HCC.

Keywords
Yttrium-90 selective internal radiation therapy
Primary hepatocellular carcinoma
Microsphere embolization
Low-dose-rate irradiation
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
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