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.
Abstract
Despite great progress in breast cancer management, metastasis, recurrence and therapeutic resistance remain major barriers to durable clinical benefit. Breast cancer stem cells (BCSCs) are now recognized as dynamic and plastic stem-like states rather than a fixed rare cell subset, shaped by epithelial–mesenchymal plasticity, hypoxia, therapeutic stress and tumor microenvironment (TME). Hybrid epithelial–mesenchymal phenotypes enable BCSCs to invade, disseminate, enter dormancy, evade immunity and form residual lesions that cause relapse. BCSCs drive resistance to chemo-, radio-, immuno-, HER2-targeted and endocrine therapies through drug efflux, antioxidant defense, DNA repair, metabolic reprogramming and alternative survival signals. Stromal and immune cells further sustain BCSC traits via cytokine crosstalk. This review summarizes the plastic features of BCSCs, their roles in metastasis and multidrug resistance, microenvironmental regulation and relevant therapeutic targeting strategies. Recent antigen-and biomarker-guided clinical trials indicate progress toward subtype-specific combination approaches, although their clinical efficacy remains to be established.
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
This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses, and highlights the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Paromita Sarker, Shreyas S Rao· Biochimica et biophysica act...· 0 citations
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.
Mehreen Ahmed, A. Al-haidari, S. Agarwal et al.· Signal Transduction and Targ...· 0 citations
Triple-negative breast cancer remains an aggressive and biologically heterogeneous breast cancer subtype. Although the therapeutic landscape has expanded, durable disease control remains clinically challenging in many settings. Existing reviews often organize TNBC therapy by drug class or molecular subtype, which can obscure how treatment response is shaped by interacting biological layers. Here, we review current and emerging therapeutic strategies through a three-layer framework: tumor-cell-intrinsic vulnerabilities, the local immune and stromal microenvironment, and host-level systemic modifiers. We summarize established approaches, including chemotherapy, immune checkpoint blockade, antibody–drug conjugates and PARP inhibition in biomarker-defined settings, and distinguish them from maturing or exploratory strategies such as pathway-directed therapy, epigenetic modulation, anti-vascular combinations, regulated cell-death induction, cellular therapy, vaccines, microbiome-related interventions, liquid biopsy, AI-supported multiomics and adaptive trial designs. This framework integrates evidence level, disease stage, biomarker reliability and patient tolerance into treatment selection for TNBC precision therapy.
Zi-Xun Wang, Xi-Yu Liu, Yu-Xiao Wu et al.· Journal of Hematology & Onco...· 0 citations
Simple Summary Colorectal cancer is often driven by a small population of colorectal cancer stem cells (CCSCs) that fuel tumor growth, metastasis, and treatment resistance, leading to relapse. These CCSCs are regulated by key signaling pathways, including Wnt/β catenin, Notch, Hedgehog, PI3K/AKT, MAPK/ERK, NF-κB, and TGF β, which are now being targeted by emerging drugs. CCSC markers and gene signatures are also under study as diagnostic and prognostic tools for early detection, minimal residual disease monitoring, and outcome prediction, although robust CCSC-specific assays and prospective clinical validation are still lacking. However, translating CCSC directed therapies into safe and effective treatments is difficult due to tumor heterogeneity, CCSC plasticity, compensatory pathways, and overlap with normal intestinal stem cell regulation. This review outlines CCSC biology, their biomarker potential, and current clinical trials targeting CCSC associated pathways, while highlighting major translational barriers that must be overcome.
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
