Aug 2026· Signal Transduction and Targeted Therapy· Vol 11· 0 citations· 499 references
Medicine
Abstract
Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.
A comprehensive synthesis of the molecular and microenvironmental mechanisms underlying CSC-driven drug resistance is provided and emerging therapeutic strategies targeting CSC plasticity, niche interactions, metabolic adaptation, and immune evasion are critically discussed.
Hayam Hamdy, Youzhou Li, Chen Li et al.· Molecular Biomedicine· 0 citations
A particular focus on the bidirectional interplay between CSCs and the tumor immune microenvironment is focused on, which may provide a conceptual framework for the development of more rational combination strategies, although their clinical benefit remains to be validated.
Jingyu Tan, Tao Wen, Jian Liu et al.· Journal of Hematology & Onco...· 0 citations
Plastic features of BCSCs are summarized, their roles in metastasis and multidrug resistance, microenvironmental regulation and relevant therapeutic targeting strategies are summarized and progress toward subtype-specific combination approaches is indicated.
Mu-Yao Li, Ying Zhou, Xin-Qi Liu et al.· Cancer Advances· 0 citations
Therapeutic resistance remains a major barrier in cancer control and is increasingly recognized as a cancer stem cell (CSC)-driven process rather than a result of residual tumor survival. CSCs sustain tumor initiation, progression, and recurrence through coordinated intrinsic and extrinsic mechanisms, including enhanced drug efflux, cellular quiescence, hypoxia tolerance, efficient DNA damage repair, metabolic adaptation, and phenotypic plasticity. These features render CSCs largely refractory to conventional chemotherapy, radiotherapy, and many molecularly targeted therapies. Although extensive efforts have focused on inhibiting CSC-associated signaling pathways, such as Wnt/β-catenin, Notch, Hedgehog, and PI3K/AKT/mTOR, clinical translation has been limited by pathway redundancy, compensatory signaling, poor tumor penetration, and systemic toxicity. Nanomaterial-based therapeutic platforms represent a promising investigational strategy with potential to address these limitations enabling multi-level intervention against CSC survival architectures. Rationally engineered nanomaterials-including metallic, carbon-based, MXene, and polymeric nanocarriers-enable multi-functional targeting of cancer stem cell resistance by enhancing intracellular delivery, modulating hypoxic niches, and inducing catalytic or photothermal cytotoxicity. These platforms integrate controlled release, ligand-mediated targeting, and microenvironment responsiveness to overcome efflux, quiescence, and repair-mediated survival pathways in CSCs. Nanomaterials bypass ATP-binding cassette transporter-mediated drug efflux, induce cell-cycle-independent cytotoxicity, remodel hypoxic niches, overwhelm DNA repair capacity, and constrain phenotypic plasticity through coordinated pathway modulation. Photothermal and catalytic nanomaterials reduce or eliminate quiescent CSC populations. while ligand-functionalized nanocarriers targeting CSC markers such as CD44, CD133, and EpCAM enhance selective delivery and intracellular drug retention. This review integrates advances in CSC biology with emerging nanomaterial-based strategies and discusses translational challenges and future directions for achieving durable cancer control through CSC-targeted nanotherapy.
K. K. Karunakar, Sowmiya Philips, Nandhini Jayaprakash· Discover Oncology· 1 citation
Cancer stem cells (CSCs) are a small population of cells within a tumor which perform stem cell like functions including self-renewal, differentiation and initiation. This narrative review aims to provide an overview of the role of CSCs in resistance to standard treatment and metastasis in breast cancer, potential treatment strategies including latest clinical trials, and the clinical implications for CSCs in the management of breast cancer. The most established breast CSC markers (CD44+/CD24- and ALDH1) are most prevalent in basal-like cancers, the most aggressive subtype of breast cancer. The most implicated CSC pathways include Hedgehog, Notch, CXCR1, and Wnt. Previous phase I/II trials targeting these pathways associated with breast CSCs have shown mixed results; no CSC-specific drug has reached phase III trial in breast cancer. To maximize the potential benefit of CSC-targeted therapy, it would be important to select or enrich patients with CSC markers or CSC-associated pathway activation. It would also be critical to develop combination strategies that overcome plasticity and/or immune invasion, and preferentially destroy CSCs with limited impact on healthy stem cells. Overall, breast CSCs may have greater clinical implications but require further research and development to realize their full clinical potential.
