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.
Abstract
Cancer therapy has advanced substantially through targeted therapies and immunotherapy; however, durable clinical responses remain limited by the development of drug resistance. Increasing evidence identifies cancer stem cells (CSCs) as central drivers of therapeutic failure, tumor recurrence, metastasis, and minimal residual disease. CSCs possess self-renewal and differentiation capacities together with remarkable adaptability under therapeutic stress, enabling long-term tumor maintenance and regeneration. CSC-mediated resistance arises through coordinated intrinsic and extrinsic mechanisms. Intrinsically, CSCs employ multiple survival programs, including cellular quiescence, enhanced DNA damage response and repair, ATP-binding cassette transporter-mediated drug efflux, apoptosis evasion, and metabolic reprogramming. Extrinsically, these mechanisms are reinforced through dynamic interactions with the tumor microenvironment (TME), particularly hypoxic and perivascular niches that support stemness and therapeutic tolerance. Importantly, CSCs are increasingly recognized as dynamic cellular states rather than fixed populations and exhibit marked plasticity through reversible transitions between stem-like and non-stem states, frequently mediated by epithelial–mesenchymal transition (EMT). This plasticity promotes intratumoral heterogeneity and replenishes resistant cell populations. In this review, we provide a comprehensive synthesis of the molecular and microenvironmental mechanisms underlying CSC-driven drug resistance and critically discuss emerging therapeutic strategies targeting CSC plasticity, niche interactions, metabolic adaptation, and immune evasion. Collectively, these insights support the development of integrated multi-target therapeutic approaches to improve long-term clinical outcomes.
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
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
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
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
Despite remarkable advances in cancer drug treatment, including chemotherapy, targeted therapy, and immunotherapy, therapeutic resistance remains a formidable clinical barrier, limiting durable responses and long-term survival. Drug resistance can be broadly categorized as intrinsic, where tumors fail to respond to initial treatment, or acquired, which emerges during or after therapy due to adaptive or evolutionary processes. A comprehensive understanding of the multifactorial and dynamic nature of resistance is essential for improving treatment efficacy. In this review, we systematically examine the molecular and cellular determinants of drug response and resistance across 22 cancer types, highlighting key resistance mechanisms such as compensatory pathway activation, phenotypic plasticity, immune evasion, enhanced DNA damage repair, and the survival of drug-tolerant persister cells. These mechanisms are further contextualized across major therapeutic modalities, supported by clinical trials. We also present emerging strategies to overcome resistance, including rational drug combinations, novel agents, microbiome modulation, adaptive and intermittent therapies and advanced drug delivery systems, each illustrated with representative clinical studies. Moreover, we discuss cutting-edge tools that are revolutionizing resistance research, including single-cell and spatial multiomic profiling, patient-derived tumor organoid and xenograft (PDO/PDX) models, and artificial intelligence (AI)-powered predictive analytics. By integrating insights across molecular, cellular, and clinical dimensions, this review offers a strategic framework for understanding and tackling cancer drug resistance, with important translational implications for the future of precision oncology.
Xiaoxiao Cheng, Miaochun Xu, Jun-cheng Wei et al.· Signal Transduction and Targ...· 1 citation
: DNA is continuously challenged by endogenous and exogenous insults, generating lesions that threaten genomic stability. Normal stem cells preserve genome integrity through highly coordinated DNA damage response (DDR) networks involving efficient base excision repair (BER), homologous recombination (HR), cell-cycle checkpoints, and TP53-mediated quality control. Cancer stem cells (CSCs), a rare tumor subpopulation responsible for tumor initiation, metastasis, relapse, and therapeutic resistance, exploit these protective mechanisms while acquiring distinct DNA repair adaptations. This review examines how stemness-associated signaling pathways, including Hedgehog, Notch, and Wnt/ β -catenin, interact with DDR programs to promote CSC survival under genotoxic stress. CSCs frequently exhibit enhanced HR activity driven by RAD51 and BRCA1/2, increased tolerance to replication stress, and sustained DNA repair capacity, contributing to resistance against chemotherapy and radiotherapy. Simultaneously, many CSC populations retain selective deficiencies in non-homologous end joining (NHEJ), nucleotide excision repair (NER), or BER, creating therapeutically exploitable vulnerabilities. We further discuss emerging DDR regulators, including HMCES-mediated protection of abasic sites and polymerase theta (Pol θ )-dependent alternative end joining, as well as the influence of tumor microenvironmental factors such as hypoxia, extracellular vesicles, and cancer-associated fibroblasts on CSC repair capacity and plasticity. We summarize current and emerging therapeutic strategies targeting CSC-specific DDR dependencies, including PARP, ATR, CHK1, and Pol θ inhibitors, replication stress-inducing agents, developmental pathway inhibitors, antibody-drug conjugates carrying topoisomerase I inhibitor payloads, and immunotherapeutic approaches. Particular emphasis is placed on synthetic-lethal strategies and biomarker-guided patient stratification using homologous recombination deficiency signatures, RAD51 foci, and SLFN11 expression. Understanding the unique DDR landscape of CSCs may facilitate the development of rational combination therapies capable of overcoming therapeutic resistance and improving long-term cancer control.
M. Kciuk, Julia Gałęziewska, Weronika Kruczkowska et al.· Oncology Research· 0 citations
