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MINI REVIEW article

Front. Oncol.

Sec. Radiation Oncology

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1640754

This article is part of the Research TopicAI-Based Prognosis Prediction and Dose Optimization Strategy in Radiotherapy for Malignant TumorsView all 7 articles

Hypoxia-inducible factor drives radiotherapy resistance and represents a therapeutic target in osteosarcoma

Provisionally accepted
Qianru  FuQianru Fu1Jinsong  LiuJinsong Liu2*
  • 1Henan University of Chinese Medicine, Zhengzhou, Henan Province, China, Zhengzhou, China
  • 2Department of Radiotherapy, Henan Cancer Hospital, Zhengzhou, Henan Province, China, Zhengzhou, China

The final, formatted version of the article will be published soon.

Osteosarcoma, the most common primary malignant bone tumor, is characterized by aggressive behavior, early metastasis, and poor prognosis, particularly in patients with advanced disease. Despite multimodal treatment involving surgery and chemoradiotherapy, therapeutic resistance remains a major challenge, partly due to the hypoxic tumor microenvironment. Hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α, play pivotal roles in osteosarcoma progression by regulating stemness, metastasis, and resistance to chemotherapy and radiotherapy. Under hypoxia, HIFs activate key pathways (TGF-β, Wnt/β-catenin, Notch, and Hedgehog) to sustain osteosarcoma stem cells (OSCs), promote multidrug resistance (MDR) via efflux transporters (MRP1/P-GP), and confer radioresistance by enhancing DNA repair and metabolic adaptation. Emerging evidence suggests that HIF inhibitorssuch as EZN-2968, curcumin, and 2-methoxyestradiol-can disrupt these pathways, sensitizing tumors to conventional therapies. This review synthesizes current knowledge on HIF-driven mechanisms in osteosarcoma and highlights the therapeutic potential of targeting HIF signaling to overcome treatment resistance and improve clinical outcomes.

Keywords: Osteosarcoma, Hypoxia-inducible factors, radioresistance, multidrug resistance, hypoxiainducible factor (HIF) inhibitors, osteosarcoma therapy

Received: 04 Jun 2025; Accepted: 16 Jul 2025.

Copyright: © 2025 Fu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Jinsong Liu, Department of Radiotherapy, Henan Cancer Hospital, Zhengzhou, Henan Province, China, Zhengzhou, China

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