REVIEW article
Front. Oncol.
Sec. Molecular and Cellular Oncology
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1643491
The Paradoxical Role of Stem Cells in Osteosarcoma: From Pathogenesis to Therapeutic Breakthroughs
Provisionally accepted
- 1West China Hospital of Sichuan University, Chengdu, China
- 2West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
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Osteosarcoma (OS), the most prevalent primary malignant bone tumor in adolescents, exhibits high metastatic potential and therapy resistance. This characteristic results in a dismal prognosis in advanced cases even with multimodal therapies. This review synthesizes the dual roles of stem cells in OS pathogenesis and therapeutic innovation. Cancer stem cells (CSCs) drive tumor initiation, progression, and chemoresistance through dysregulated molecular pathways including Wnt/βcatenin, Notch, and Hedgehog signaling, with key markers such as CD133 and CXCR4 contributing to stemness maintenance and metastasis. Concurrently, mesenchymal stem cells (MSCs) paradoxically influence OS progression: while their tumor-homing capacity enables targeted drug delivery (e.g., IDD-1040-paclitaxel complexes) and immunomodulation, MSC-derived factors like TGF-β can promote cancer-associated fibroblast differentiation and immune evasion.The immunosuppressive tumor microenvironment (TME), characterized by hypoxia-induced HIF-1α activation, metabolic reprogramming, and M2 macrophage polarization, further facilitates CSC resilience and therapy resistance. Emerging strategies-including CSCs-targeted agents (AZD1080, DNMTi/HDACi), CRISPR/Cas9-engineered CD133-directed CAR-T cells, and MSC-mediated delivery of oncolytic viruses-show preclinical promise in overcoming these barriers. However, critical challenges persist: intratumoral CSC heterogeneity limits targeted therapy efficacy; MSC functional plasticity risks tumor promotion via fusion or batch variations; and inefficient cell homing due to pulmonary entrapment reduces therapeutic delivery.Future directions necessitate biomarker-guided combinatorial approaches, optimized MSC administration routes (e.g., intra-arterial injection), and integrated multi-omics profiling to address translational bottlenecks. Resolving these issues will advance personalized stem cell-focused therapies for OS.
Keywords: Osteosarcoma, cancer stem cells, Mesenchymal Stem Cells, regulatory mechanisms, Translational barriers
Received: 09 Jun 2025; Accepted: 06 Aug 2025.
Copyright: © 2025 Su, Fang and Duan. 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: Hong Duan, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
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