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Review

Cancer Stem Cells in Breast Cancer: Unlocking New Frontiers in Therapeutic Strategies

Qamre Alam1★, Reem Saeed Alazragi2, Alaa Al-Kathiri3, Alrayan Abass Albaz4, Jawaher Mohammad Alshehri5, Fatimah Ali Alsaffar6, Dalia Alammari7,8, Saleh Alqahtani9★ Corresponding author

  1. 1Department of Molecular Genomics and Precision Medicine, EXPRESSMED Diagnostics and Research, Zinj, BAHRAIN.
  2. 2Department of Biological Sciences, College of Science, University of Jeddah, Jeddah, SAUDI ARABIA.
  3. 3College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Jeddah, SAUDI ARABIA.
  4. 4Department of Oncology and Human Metabolism, Molecular Medicine Genetics, The Medical School, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UNITED KINGDOM.
  5. 5Department of Optometry, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, SAUDI ARABIA.
  6. 6Department of Medical Laboratory Science, AlGhad College for Applied Medical Sciences, 4177 Al Nabighah Al Dhubyani - Al Zahour District, Dammam, SAUDI ARABIA.
  7. 7Department of Immunology and Pathology, Faculty in Medicine Program, Ibn Sina National College for Medical Studies, Jeddah, SAUDI ARABIA.
  8. 8Health Professions Education Center, Ibn Sina National College for Medical Studies, Jeddah, SAUDI ARABIA.
  9. 9Department of Haematology, King Faisal Medical City for Southern Regions, Abha, SAUDI ARABIA.

CORRESPONDENCE

Qamre Alam

Molecular Genomics and Precision Medicine Department, EXPRESSMED Diagnostics and Research, Zinj, BAHRAIN.

alamqa2022@gmail.com

Received: 03-09-2025; Revised: 22-10-2025; Accepted: 16-12-2025.

Volume 16, Issue 2 · pp. 523–535 · PUBLISHED Apr-Jun 2026 · DOI: 10.5530/ijpi.20260153

View on IJPI original site ↗

ABSTRACT

This review thoroughly examines Breast Cancer Stem Cells (BCSCs) discussing their involvement, in tumor advancement and spread and their resistance to treatment while also discussing methods for targeting them for elimination purposes. We delve into indicators as well as the signaling pathways that control their ability to regenerate and survive; we also explore different treatment methods such as small molecule inhibitors and immune based therapies along with newer technologies, like RNA interference techniques, CRISPR/Cas9 applications and drug delivery systems driven by nanotechnology. Furthermore, it deals with the difficulties presented by adaptability, tumor diversity and interactions, within the microenvironment alongside the requirement for enhanced models and successful clinical application. The analysis brings into focus existing progressions, constraints and forthcoming paths in BCSC focused treatments underscoring their ability to improve results, in breast cancer therapy.

KEYWORDS

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FULL TEXT

INTRODUCTION

Breast cancer is the most frequent cancer and the leading cause of cancer mortality among women globally. It is a very complex disease consisting of different molecular subtypes like luminal A, luminal B, HER2-enriched and Triple-Negative Breast Cancer (TNBC) which have different behavior and response to treatment (Testa et al., 2020). Nevertheless, there has been a significant enhancement in the early diagnosis and treatment of the disease, relapse, metastasis and therapy resistance are still a problem.

Surgery, chemotherapy, radiotherapy, hormonal therapy and targeted therapy are the conventional breast cancer treatments. Endocrine therapies such as tamoxifen and aromatase inhibitors are effective in hormone receptor positive breast cancers while trastuzumab is used in the treatment of HER2 positive cases (Montagna et al., 2019). However, TNBC does not have hormone receptors and HER2 expression is treated poorly and is aggressive and likely to recur. One of the biggest problems in breast cancer therapy is the development of resistance to the drugs which can be intrinsic (before the treatment) or acquired during the course of treatment (Nikolaou et al., 2018). The processes that lead to the development of resistance include genetic mutations, epigenetic changes, the activation of signaling pathways and interactions with the tumor microenvironment. These mechanisms allow cancer cells to become resistant to the cytotoxic effects of the drugs resulting in treatment failure and disease progression. Metastasis is another important issue because breast cancer can spread to other parts of the body including the lungs, liver, bones and brain. Metastatic Breast Cancer (MBC) is generally incurable and current therapies are mainly palliative, aimed at increasing the length of life and enhancing the quality of life. Cancer Stem Cells (CSCs) have been found to play a crucial role in the propagation of tumors, metastasis and therapy resistance, and are a rare subset of cells in the tumor (Yadav et al., 2019). These CSCs possess the ability to self-renew, to differentiate and to escape from the conventional treatments, and thus are an important candidate for new treatment strategies.

CSCs are a subpopulation of tumor cells that have the capacity to self-renew and to differentiate into multiple cell types, and are thought to be involved in the initiation of a tumor, its progression, and the development of resistance to treatment. These cells are similar to normal stem cells but their signaling pathways are dysregulated to lead to tumorigenesis. CSCs were first found in haematological malignancies and have since been found in solid tumors including breast cancer (Kai et al., 2010). The existence of CSCs explains tumor heterogeneity, treatment failure and recurrence. CSCs are thought to be derived from normal stem or progenitor cells that have undergone mutations that enable them to sustain self-renewal and to initiate tumorigenesis. In contrast to conventional cancer cells that have limited proliferative capacity CSCs can give rise to the entire tumor mass. In breast cancer, CSCs are defined by surface markers such as CD44+ / CD24-, Aldehyde Dehydrogenase 1 (ALDH1) (Zhang et al., 2020). These markers are linked with aggressive tumor behaviour, poor prognosis and therapeutic resistance. Metastasis is the major cause of cancer death and is driven in part by CSCs. These cells have increased migratory and invasive capabilities that allow them to leave the primary tumor, survive in the circulation, and colonize distant organs. The EMT (epithelial-to-mesenchymal transition) is involved in this process, whereby epithelial-like cancer cells assume mesenchymal characteristics to enhance their motility and resistance to apoptosis. Breast cancer stem cells are highly EMT active and can thus avoid immune surveillance and form metastases.

CSCs are a significant cause of therapy resistance and are therefore a major problem in breast cancer management (Bai et al., 2018). They have numerous mechanisms of resistance. The bulk tumor cells are usually proliferating rapidly, but CSCs are usually in a quiescent or relatively slow-cycling state and thus are relatively protected from the cytotoxic effects of chemotherapeutic agents that are designed to target mitochondria of actively proliferating cells. In addition, CSCs have high expression of ATP-Binding Cassette (ABC) transporters such as ABCG2 and P-glycoprotein that efflux the chemotherapeutic drugs from the cytoplasm decreasing the effectiveness of the drugs. Furthermore, CSCs have increased capacity to repair DNA damage which enables them to survive the genotoxic stress associated with radiation and chemotherapy. In addition, CSCs also manifest defective apoptotic pathways whereby they over express anti-apoptotic proteins like BCL-2, Survivin to name but a few that enable them to survive while under therapeutic pressure (Babikian et al., 2020). Finally, CSCs are located in specific niches within the TME where stromal cells, immune cells, and the extracellular matrix provide cytokines that sustain them during therapy induced stress.

The main reason for targeting BCSCs is their role in tumor heterogeneity and plasticity. BCSCs can shift their phenotype between epithelial and mesenchymal states and, therefore, can easily change their phenotype in response to the alterations in the microenvironment. This plasticity makes BCSCs to evade the therapeutic pressure and remain a source of tumor recurrence even after aggressive treatments. Thus, the eradication of the pathways Controlling BCSC plasticity such as Wnt, Notch and Hedgehog signaling may be beneficial in decreasing tumor plasticity and enhancing the response to therapy. Moreover, BCSCs play an important role in metastasis which is the major cause of death from breast cancer. These cells have increased levels of invasion and migration, which enable them to leave the primary tumor, circulate in the bloodstream and form metastases in other organs. Conventional treatments are usually inadequate to kill these circulating tumor stem cells thereby leading to disease progression and recurrence. Inhibition of BCSCs with particular inhibitors or immunotherapeutic strategies may help to prevent metastatic spread and enhance patient survival time.

An additional crucial aspect of BCSC biology that makes them an attractive therapeutic target is their resistance to conventional therapies. Chemotherapy and radiotherapy affect primarily rapidly dividing cells; however, BCSCs are slow-cycling or quiescent and thus escape treatment. Furthermore, these cells have strong DNA repair mechanisms, drug efflux transporters at high expression levels, and resistance to apoptosis, which also contribute to therapeutic failure. Metabolic inhibitors, epigenetic modulators, and RNA-based therapies that attack this resistance mechanisms might make BCSCs more amenable to treatment and less likely to return. Last, the notion of targeting BCSCs offers an opportunity to enhance the standard therapies and patient results. Combining CSC-targeted therapies with conventional treatment may allow killing of both CSCs, as well as the differentiated cancer cells and prevent tumor regrowth and lead to better long term remission rates. If future breast cancer therapies are to move away from tumor control and towards cure, then targeting BCSCs may be required to eliminate tumor cell self-renewal.

Characteristics of BCSCs

Markers

Identifying and characterizing BCSCs is crucial to developing strategic therapeutic approaches. Numerous cell surface and intracellular markers have been employed to define and sort out BCSCs, including CD44+ / CD24-, aldehyde dehydrohydrogenase 1 (ALDH1), and epithelial cell adhesion molecule (EpCAM). These markers are stemness markers and are also associated with the self-renewal capacity and tumorigenic potential of the cells.

The most well-known BCSC marker to date is the CD44+ / CD24- phenotype (Romaniuk-Drapała et al., 2024). CD44 is a transmembrane glycoprotein that is involved in cell adhesion, migration, and interaction with the tumor microenvironment, whereas CD24 is a surface protein that is mainly found in differentiated cells. BCSCs usually have high levels of CD44 and low levels of CD24 (CD44+ / CD24-), which has been connected to increased invasiveness, apoptosis resistance, and increased tumorigenicity. CD44+ / CD24- cells, which were isolated from breast tumors, have been shown to have a higher tumor-initiating capacity in xenograft models than non-CSCs. The CD44 receptor is also involved in the maintenance of CSC plasticity by binding to hyaluronic acid and activating key signaling pathways such as PI3K/AKT, Wnt/beta-catenin, and Hedgehog, thus making it a possible therapeutic target (Xu et al., 2022).

The other marker that is critical for BCSCs is Aldehyde Dehydrogenase 1 (ALDH1), an intracellular enzyme that is involved in detoxification, oxidative stress regulation, and the metabolism of retinoic acid. Elevated ALDH1 activity has been characterized as a feature of stem-like cancer cells that possess increased self-renewal capacity, enhanced resistance to chemotherapy, and tumorigenicity. In initial experiments, ALDH1-positive BCSCs have been found to form tumors more effectively than ALDH1-negative cells (Elbaiomy et al., 2020). Of particular importance, ALDH1 expression is also related to worse prognosis and more frequent relapse in breast cancer patients. CD44+ / CD24-, which mainly marks mesenchymal-like BCSCs, is different from CD44. ALDH1 expression is often linked to epithelial-like CSC populations, which shows the heterogeneity of BCSCs (Elbaiomy et al., 2020).

Epithelial Cell Adhesion Molecule (EpCAM) is another surface marker that is frequently employed in the characterization of BCSCs. EpCAM participates in cell adhesion and signaling and its level is increased in cells with high proliferative potential, stemness and tumorigenicity (Conde et al., 2022). EpCAM+ BCSCs have been found to participate in tumor formation and metastasis and their presence is related to a worse prognosis (Wu et al., 2019). Also, EpCAM is involved in the maintenance of epithelial phenotype, which allows to distinguish between epithelial-like BCSCs and their mesenchymal counterparts. In addition to these primary markers, the CD133, Sox2, Oct4, and Nanog proteins have been implicated in the biology of BCSCs (Song et al., 2021). These markers are linked to pluripotency, self-renewal, and therapy resistance. The complexity of BCSCs indicates that a single marker cannot capture the entire population; rather, a set of markers is usually employed to sort and classify these cells.

Role in tumor progression, metastasis and resistance

Metastasis is a complicated multi-step process that involves the shedding of tumor cells from the parent tumor, their penetration through the surrounding tissues, their penetration into the blood stream, and their lodgement in other organs including the lungs, liver, bones and brain. Due to their ability to undergo EMT (Epithelial-Mesenchymal Transition), BCSCs are well positioned for this process since they are known to possess the marked capacity to undergo EMT, a phenotypic change that enhances cell motility, invasiveness, and resistance to anoikis (apoptosis induced by the lack of cell adhesion). EMF reduces the expression of E-cadherin, a typical epithelial marker, and increases the levels of N-cadherin and vimentin, markers of mesenchymal cells, which enable the cells to migrate and invade (Fiori et al., 2019). When the BCSCs arrive at a distant organ, they can return to an epithelial-like state through the reverse process known as the Mesenchymal-Epithelial Transition (MET), and form new tumor colonies and promote metastatic growth.

BCSCs are also very resistant to conventional therapies including chemotherapy, radiotherapy, and targeted therapies, and are a major determinant of treatment failure and disease relapse. One important mechanism of resistance is their quiescent or slow-cycling phenotype that renders them relatively insensitive to the chemotherapeutic agents that are designed to target mitotically active cells. Moreover, the BCSCs possess increased levels of ATP-Binding Cassette (ABC) transporters, including ABCG2 and P-glycoprotein that efflux the chemotherapeutic drugs from the inside of the cell, thus decreasing the intracellular concentration of the drugs and the effectiveness of treatment (Modi et al., 2022). Furthermore, BCSCs have increased capacity to repair DNA and are thus able to survive the genotoxic stress associated with radiation and chemotherapy. This is further augmented by their apoptosis resistance, which is sustained by the overexpression of anti-apoptotic factors, including BCL-2 and survivin.

There is another major factor that is responsible for the therapy resistance and that is the interaction of BCSC with the TME (Tumor Microenvironment). The TME is composed of stromal cells, immune cells, extracellular matrix components and secreted cytokines and it creates a protective environment that allows BCSCs to survive and self-renew. The Cancer-Associated Fibroblasts (CAFs) and TAMs produce cytokines that support the stemness and therapy resistance of CSC (Gaggianesi et al., 2021). Moreover, the hypoxic areas of the tumors stimulate the HIFs, which in turn activate the survival pathways of BCSCs such as Notch and Wnt signaling. The protective interactions in the TME are therefore a major problem in the attempt to eliminate BCSCs with conventional treatments.

Signaling pathways regulating BCSCs

Several signaling pathways are there that regulate the BCSCs and their differentiation. The Wnt signaling pathway is necessary for the preservation of the BCSCs’ stemness and self-renewal (Weerackoon et al., 2021). The canonical Wnt signaling pathway is triggered when Wnt ligands interact with Frizzled receptors and low-density Lipoprotein Receptor-Related Protein (LRP) co-receptors, which result in the stabilization and nuclear localization of β-catenin (Hu et al., 2024). Once in the nucleus, β-catenin interacts with transcription factors to activate genes that are involved in stemness, proliferation, and survival. The Wnt pathway is therefore dysregulated in BCSCs, which in turn increases the propensity of forming tumors, becoming therapy resistant, and metastasizing. Nevertheless, non-canonical Wnt signaling, which occurs independently of β-catenin, has been found to regulate BCSC plasticity and migration. Blocking Wnt signaling with small molecule inhibitors or monoclonal antibodies seems like a good way to deplete BCSCs and thus improve the overall treatment results.

Another important pathway that regulates the BCSCs and their differentiation is the Notch signaling pathway. Notch signaling is switched on by the binding of Delta-like or Jagged ligands to Notch receptors, which results in cleavage of the Notch Intracellular Domain (NICD) (Wang et al., 2022). NICD is released into the nucleus where it triggers the expression of genes that are involved in stemness, proliferation and apoptosis resistance. Aberrant Notch signaling in BCSCs leads to tumor growth, metastatic spread, and resistance to chemotherapy and radiotherapy. Notch signaling also participates in the crosstalk between BCSCs and the TME by facilitating immune suppression and angiogenesis. In vitro studies have shown that inhibitors of γ-secretase, an enzyme required for the activation of Notch, can eliminate BCSCs and improve the efficacy of standard therapies (Ray et al., 2024).

The Hh signaling pathway is required during embryonic development and tissue regeneration, but it is overactivated in different cancers, including breast cancer. The Hh pathway is activated when one of the Hh ligands (Sonic Hedgehog, Indian Hedgehog, or Desert Hedgehog) binds to the patched receptor, which in turn removes the inhibition of transmembrane protein Smoothened (SMO) (Jing et al., 2023). This results in the activation of Gli transcription factors that induce the expression of genes that support the self-renewal, cell survival, and chemoresistance phenotype (Citarella et al.,, 2023). Hedgehog signaling pathway is responsible for the aggressive nature of the tumor and therapy resistance through the maintenance of stemlike properties and EMT. Small molecule inhibitors of SMO or Gli transcription factors are potentially useful for the treatment of BCSC-driven tumor growth.

The PI3K/AKT signaling pathway is involved in the regulation of cell survival, metabolism, and proliferation of breast cancer, including BCSCs. The activation of Phosphoinositide 3-Kinase (PI3K) is auto- or paracrine through Receptor Tyrosine Kinases (RTKs) or G protein-coupled receptors, which results in the activation of AKT through phosphorylation. This cascade brings about survival by suppressing apoptosis and increasing the expression of stemness markers. The PI3K/AKT pathway is cross talked with Wnt and Notch pathways to sustain BCSCs and to make them resistant to targeted therapies (Jan et al., 2025). Mutations in components of the PI3K pathway, including PIK3CA, are common in breast cancer and confer resistance to therapy. Current studies are ongoing on the use of PI3K and AKT inhibitors to kill BCSCs and make the tumors sensitive to conventional treatments.

Other pathways, such as JAK/STAT, NF-κB, and Hippo/YAP, also participate in the maintenance of BCSCs and resistance (Shabna et al., 2023). These pathways are interlinked in a combinatorial manner to support the stemness and adaptive outcome of BCSCs during the stress of therapy. It is, therefore, important to know the detailed mechanisms of crosstalk between these signaling pathways in order to design effective combination therapies that can home in on BCSCs and prevent tumor recurrence.

Therapeutic strategies targeting BCSCs

The therapeutic approaches aimed at BCSCs aim at the elimination of their stemness, that is their ability to self-renew and to resist conventional treatments. Inhibitors of small molecules that target Wnt, Notch and Hedgehog pathways disrupt the signaling networks that are critical in maintaining BCSCs. Monoclonal antibodies, checkpoint inhibitors of the immune system, and CAR T/NK cell therapies help the immune system to recognize and kill the BCSCs. Also, therapeutic approaches like siRNA, miRNA and CRISPR/Cas9 based gene editing are used to modulate the stemness associated genes precisely. Nanoparticle based drug delivery and combination therapy with chemotherapy or radiation therapy increases the treatment outcome and also decreases the probability of relapse (Figure 1).

Figure 1: Hypothetical model showing integrated multi-targeted therapy for BCSC eradication.

Small molecule inhibitors

Using small molecule inhibitors of self-renewal pathways of BCSCs has been proposed to target therapy resistant tumor cells and prevent recurrence. The Wnt, Notch and Hedgehog signaling pathways are crucial to the self-renewal, survival and plasticity of BCSCs and their aberrant activation is involved in tumor progression, metastasis and resistance to standard treatment. The pathways are currently under investigation in preclinical and clinical studies for the development of small molecule inhibitors as novel therapeutic agents for breast cancer.

Wnt pathway inhibitors are meant to prevent the hyperactivation of β-catenin signaling that is required for the stem like properties of BCSCs. Among them, small molecules that target Wnt ligands, Frizzled receptors or downstream β-catenin activity have been developed. LGK974 is a porcupine inhibitor and has the potential to decrease BCSC populations in breast cancer models through the inhibition of Wnt ligand secretion (Romaniuk-Drapała et al., 2024). XAV939 is a tankyrase inhibitor that enhances the degradation of β-catenin and suppresses Wnt driven tumor growth (Das et al., 2025). Furthermore, PRI-724, a CBP/β-catenin interaction inhibitor, prevents the transcription of Wnt target genes and decreases the formation of BCSCs that lead to tumor initiation (Peri et al., 2023). However, like other Wnt inhibitors, these compounds have toxicity issues and also, the Wnt pathway is important in the normal tissue homeostasis, and thus, has a complex redundancy.

Notch signaling pathway is also a crucial therapeutic target in BCSCs, their maintenance, survival and therapy resistance. γ Secretase Inhibitors (GSIs), such as DAPT and RO4929097, inhibit cleavage of Notch receptors, which prevents the release of NICD and subsequent gene activation (Wang et al., 2024). These inhibitors have shown the capacity to affect the self-renewal of BCSC and to render tumors more sensitive to chemotherapy and radiotherapy. Nevertheless, owing to the important role of Notch signaling in normal tissue development and immune function, systemic toxicity is still a major problem. Newer, more specific Notch inhibitors are being explored, such as CB-103, which specifically targets NICD transcriptional activity. Monoclonal antibodies against Notch receptors like Brontictuzumab (against Notch1) are also being investigated to increase the specificity and decrease the side effects.

The Hh signaling pathway is also a crucial determinant of the BCSC self-renewal and drug resistance. Many Hedgehog inhibitors have been created to inhibit SMO, a key activator of the pathway. Vismodegib (GDC-0449) and Sonidegib (LDE225) are SMO inhibitors approved for basal cell carcinoma and are being investigated in breast cancer (Lear et al., 2023). These inhibitors act on BCSCs through the suppression of Gli transcription factors to prevent tumor growth. However, SMO inhibitors are known to develop resistance through mutations in the downstream signaling effectors, such as SUFU and Gli proteins. To overcome this, direct Gli inhibitors such as GANT61 are being investigated as an alternative strategy (Wang et al., 2024).

Beside small molecules, epigenetic regulation is also involved in the sustainment of the plasticity, self-renewal, and therapy resistance of BCSCs. While genetic mutations result in changes in the DNA sequence, epigenetic modifications involve reversible changes in gene expression through DNA methylation, histone modifications, and chromatin remodelling. These epigenetic mechanisms are utilized by BCSCs to sustain their stem-like properties and escape standard regimens. Hence, inhibition of epigenetic modifiers, including Histone Deacetylase (HDAC) and DNA Methyltransferase (DNMT) inhibitors, is a promising concept to target BCSCs and treat therapy resistance. HDAC inhibitors are under consideration as anti-BCSC agents because they can reverse the abnormal epigenetic silencing and induce the differentiation of CSCs to non-tumorigenic cells (Landeros et al., 2023). HDACs deacetylate histones, thereby causing chromatin compaction and suppression of the expression of tumor suppressor genes. HDAC activity is inhibited, thereby allowing the expression of differentiation-associated genes and the sensitization of BCSCs to chemotherapy. Vorinostat (SAHA) and Panobinostat have been found to display preclinical efficacy in decreasing BCSCs through the inhibition of stemness pathways such as Wnt, Notch, and Hedgehog in preclinical studies (Alalhareth et al.,, 2025; Jung et al.,, 2024). Entinostat, a selective HDAC1/HDAC3 inhibitor, has been found to have potential to suppress the self-renewal of BCSCs and improve the response to immune checkpoint inhibitors in breast cancer models (Jung et al.,, 2024). Further, the use of DNMT inhibitors to target aberrant DNA hypermethylation, a mechanism by which BCSCs keep tumor suppressor genes silenced and thus undifferentiated, has been explored. DNMT inhibitors such as AZA (5-azacytidine) and DAC (decitabine) are incorporated into DNA and counteract the function of DNMT, resulting in the reactivation of genes that are involved in differentiation, apoptosis and immune recognition (Zhou et al., 2023). DNMT inhibitors have been found to decrease the BCSC fractions and make the tumors more sensitive to the standard treatments in breast cancer. Moreover, the combination of DNMT and HDAC inhibitors has been found to have synergistic effects in the reversal of epigenetic reprogramming of BCSCs, thus increasing the curative potential.

Beyond HDAC and DNMT inhibitors, other epigenetic modulators, including Bromodomain and Extra-Terminal (BET) inhibitors, and EZH2 inhibitors are investigated for their role in regulating BCSC (Kim et al., 2023; Mahendran et al., 2024). BET inhibitors such as JQ1 block the binding of BET proteins to acetylated histones, which blocks the transcriptional programs that support CSC propagation (Gargano et al., 2023). EZH2 is a key component of the Polycomb Repressive Complex 2 (PRC2), which catalyses histone methylation and suppresses the expression of differentiation-related genes. EZH2 inhibitors such as Tazemetostat have been found to reverse CSC associated epigenetic alterations and decrease tumor propagating capacity. Epigenetic modulators are therefore a new class of targets for the elimination of BCSCs, by erasing the genes that enable stemness and treatment resistance. However, issues including, side effects, toxicities, and the dynamic nature of epigenetic modifications are still a concern (Masoudi et al.,, 2024). Current studies and clinical investigations are aimed at enhancing these agents and finding ways to combine them with other therapies to enhance the overall outcomes of breast cancer treatment.

BCSCs have specific metabolic changes that enable them to sustain themselves, proliferate and tolerate therapy. Not like the general tumor cells which have their metabolism based on the glycolytic pathway (Warburg effect), BCSCs are able to switch between the glycolytic and Oxidative Phosphorylation (OXPHOS) depending on the conditions (Ali et al., 2024). This metabolic flexibility allows BCSCs to endure stress, resist standard treatments, and cause tumor recurrence. Metabolic pathways such as mitochondrial metabolism, glycolysis and lipid metabolism have been identified as possible targets in the efforts to eliminate BCSCs. The application of mitochondrial inhibitors to block OXPHOS and ATP production in BCSCs is also being investigated. Most BCSCs, especially in the hypoxic regions of the tumor, depend on mitochondria for energy production. Metformin, a commonly used oral diabetes drug, has been found to have a strong effect on targeting BCSCs by attacking mitochondrial complex I, decreasing ATP production and inducing oxidative stress apoptosis (Ali et al., 2024). Other OXPHOS inhibitors such as IACS-010759 that targets mitochondrial complex I has also been found to be effective in targeting BCSCs by disturbing their metabolic homeostasis (Jiao et al., 2023). Moreover, MitoQ, a mitochondria-targeted antioxidant, induces ROS imbalance in BCSCs, leading to their selective elimination (Rondeau et al., 2024). Inhibitors of glycolysis aim at the increased glucose metabolism which is a characteristic of BCSCs and prevents these cells from meeting their energy requirements. 2-Deoxy-D-glucose (2-DG) is a glucose analog that acts as a competitive inhibitor of hexokinase, the first enzyme of glycolysis, resulting in ATP depletion and death of the glycolysis-dependent BCSCs (Zhuo et al., 2020). Lonidamine is also a glycolysis inhibitor that interferes with hexokinase and mitochondrial functions, that leads to energy deprivation and reduction in tumorigenicity (Orlovskiy et al., 2024). Furthermore, Dichloroacetate (DCA) acts as PDH activator, thereby switching the metabolism from glycolysis to OXPHOS and hence increases the sensitivity of BCSCs to apoptosis (Schoenmann et al., 2023). Besides the two major metabolic pathways of glycolysis and OXPHOS, BCSCs also depend on lipid metabolism for their survival and therapy resistance. Enhanced Fatty Acid Oxidation (FAO) has been associated with the propagation of BCSCs and their metastasis. Etomoxir, a CPT1 (Carnitine Palmitoyltransferase) inhibitor, blocks FAO and affects the energy equilibrium in BCSCs, thus rendering them more vulnerable to chemotherapy (Du et al., 2024). That, in turn, opens new possibilities for using statins, inhibitors of cholesterol synthesis, for the suppression of BCSC proliferation and self-renewal. Metabolic targeting strategies are particularly effective when used in conjunction with conventional therapies, and BCSCs often evade treatment by altering their metabolic state. These inhibitors significantly hold promise to overcome therapy resistance and decrease tumor recurrence in breast cancer by disrupting key metabolic pathways. However, challenges like systemic toxicity, metabolic compensation, and patient heterogeneity must be addressed to enhance their clinical effectiveness to the maximum.

Immunotherapy approaches

Antibodies to BCSC markers are attached to monoclonal antibodies, which are now coming out as a potential means of selectively killing BCSCs with minimal effect on normal cells. BCSCs are characterized by the expression of specific surface markers, such as CD44+CD24-, ALDH1, and EpCAM, which differentiate them from general tumor cells and are required for their self-renewal, survival, and metastasis. Monoclonal antibodies act by recognizing these markers, blocking their signaling, and inducing immune-mediated cytotoxicity and the efficacy of conventional therapies. Antibodies to CD44 have been studied in detail because CD44 is involved in the regulation of BCSC stemness, tumor progression, and chemotherapy resistance (Saha et al., 2022). CD44 interacts with Hyaluronic Acid (HA) present in the tumor microenvironment and triggers signaling pathways such as PI3K/AKT and MAPK. The CD44 monoclonal antibody RG7356 exhibits anti-tumor activity by interfering with CD44 signaling and promoting ADCC (Antibody-Dependent Cellular Cytotoxicity) (MacLean et al., 2024). Moreover, the existence of bispecific antibodies that recognize CD44 and immune checkpoint molecules is under investigation to improve immune attacks on BCSCs.

Epithelial Cell Adhesion Molecule (EpCAM) a known marker for BCSC plays a role in cell adhesion and tumor progression processes in the body. Researchers have been exploring the use of Catumaxomab - an antibody that targets both EpCAM and CD3 for treating EpCAM positive cancers by activating T cells to eliminate BCSCs (Gamage et al., 2023). Another antibody known as Edrecolomab has also been tested in trials as a treatment option for EpCAM related conditions (Dogbey et al., 2024.).; however, its effectiveness varies among individuals. Innovative Antibody Drug Conjugates (ADCs) that focus on targeting EpCAM are currently, under development to improve the destruction of BCSC specifically. Antibodies that target ALDH (Aldehyde Dehydrogenase 4 Family Member A Protein) known for its Role in detoxifying Oxygen Species (ROS) and supporting the survival of BCSC are currently under investigation in early-stage development efforts [51] as therapies when used in combination with chemotherapy or immune checkpoint inhibitors to improve treatment outcomes for patients with breast cancer. In addition to the focus on ALDH targeting antibodies and their potential benefits for survival under stress conditions and ROS detoxification processes is being explored further through investigating monoclonally targeting other proteins associated with BCSC like CD133 and CD47 along with integrins to broaden the scope of treatments available, for breast cancer patients (Ali et al., 2024). CD133 targeting antibodies have displayed potential, in animal studies by reducing the ability of tumors to grow and spread; on the hand antiCD47 antibodies are designed to boost the ability of cells called macrophages to eliminate breast cancer stem cells through phagocytosis. Volociximab which targets integrin like aβ integrin disrupt cell adhesion and invasion thus limiting the spread of cancer to other parts of the body (Teoh et al., 2025; Ranga et al., 2025). Immune Checkpoint Inhibitors (ICIs) have greatly changed cancer therapy by enhancing anti-tumor immunity and there is growing interest in their use in the management of BCSCs. BCSCs possess immune-evasive capabilities that include the expression of immune checkpoint molecules such as PD-1/PD-L1 (programmed death-1) and CTLA-4, which enable them to evade immune surveillance and promote tumor growth and therapy resistance. ICIs work by reversing this suppression, thereby enabling the immune system to act against BCSCs. PD-1/PD-L1 Inhibitors have shown promising results in breast cancer, especially in TNBC where BCSCs are enriched. PD-1 is an inhibitory receptor on T cells; its ligand, PD-L1, is overexpressed on BCSCs and tumor-associated immune cells. This interaction checks T cell activation, thereby enabling BCSCs to escape immune surveillance. The FDA-approved PD-1/PD-L1 inhibitors, including Pembrolizumab (anti-PD-1) and Atezolizumab (anti-PD-L1), have demonstrated clinical benefit in TNBC by reactivating T cells against tumors. Preclinical studies suggest that BCSC populations are particularly sensitive to PD-1/PD-L1 blockade, especially when combined with chemotherapy or radiation therapy, which increases PD-L1 expression on cancer cells.

CTLA-4 (Cytotoxic T-Lymphocyte Associated Protein 4) Inhibitors act on still one more immune checkpoint that controls T cell activation. CTLA-4 is an inhibitory receptor on T cells that acts by competing with CD28 for B7 ligands binding and thus down modulating the immune responses. BCSCs use CTLA-4 signaling to sustain an immunosuppressive microenvironment. Ipilimumab, a CTLA-4 blocking antibody, has been investigated in breast cancer and has shown potential in improving T cell infiltration into the tumors. However, owing to its systemic immune activating properties, CTLA-4 blockade is usually accompanied by higher immune related toxicities (Zhang et al., 2023). Combination of immune checkpoint inhibitors with other BCSC targeting therapies is believed to be a promising way of circumventing resistance. Epigenetic modulators, such as DNMT and HDAC inhibitors, are believed to increase the expression of immune checkpoint ligands on BCSCs thus making them amenable to ICIs. Also, metabolic reprogramming strategies, including OXPHOS inhibitors, may remove the energy advantage of BCSCs and thus make them more vulnerable to immune attack.

Cancer vaccines

Cancer vaccines are a novel type of immunotherapy that seek to induce an immune response against the BCSCs. This is because conventional therapies are known to fail to eliminate BCSCs due to their immune evasion but cancer vaccines improve on the durability of immune memory to decrease the likelihood of tumor return or spread. Dendritic Cell (DC)-based vaccines, peptide-based vaccines, and whole-cell vaccines are under investigation for the possibility of targeting BCSCs in breast cancer (Keshavarz et al., 2023). In addition to the challenges associated with CSCs, the management of breast cancer is also hindered by the ineffectiveness of current therapeutic approaches that result in Normal Stem Cell (NSC) damage.

Dendritic Cells (DCs) are Antigen Presenting Cells (APC) of professional type, which are involved in the initiation of antitumor immunity. Anti-tumor immunity is primed by DC based vaccines by recognizing BCSC specific antigens and stimulating T cells to induce cytotoxic responses. These vaccines are made by extracting patient’s DCs, presenting them with Tumor Associated Antigens (TAAs) or BCSC markers (CD44, EpCAM, ALDH1) then returning them to the patient to stimulate an immune response against the tumor. Sipuleucel-T is one of the most investigated DC based vaccines in breast cancer despite being initially developed for prostate cancer and showing a way for BCSC targeted immunotherapy (Gul et al., 2021). The previous studies have demonstrated that BCSC specific DC vaccines are effective in inducing T cells to recognize and kill BCSCs, and this combination may be particularly effective when used with immune checkpoint inhibitors or chemotherapy (Vasileiou et al., 2024).

Peptide based vaccines employ short sections of tumor antigens to trigger reactions, against BCSCC cells in the body. They commonly target antigens like Mucin. 11 HER 22 and Survivin that are often found in amounts in BCSCC cells (Pallerla et al., 2021). The E75 peptide vaccine, known as Nelipepimut S hails from the HER 22 protein has demonstrated potential in diminishing breast cancer recurrence rates by boosting HER 22. CTL responses (Liu et al., 2023). On the other hand, whole cell vaccines such, as GVAX utilize engineered tumor cells to elicit a broad immune reaction (Swathi et al., 2025). These vaccines have the potential to improve their effectiveness, in eradicating cancer cells that're resistant to treatment by incorporating BCSC related markers into their design. The use of CAR T cell therapy has shown promise in combating BCSCs (Yang et al., 2022). This involves modifying T cells to identify and remove these cell populations effectively.

Chimeric antigen receptor CAR T cells are altered at the level to produce receptors that can recognize specific BCSC related markers, like CD44 EpCAM and HER2 (Manian et al., 2025). CAR T cells differ from T cell responses as they can identify tumor antigens without relying on histocompatibility complex which enhances their ability to target immune evading BCSC cells effectively.

The current literature suggests that CD44 directed CAR-T cells can effectively eliminate BCSCs and suppress tumor growth in breast cancer preclinical models. As CD44 is a crucial determinant of BCSCs’ self-renewal and metastasis, CAR-T cell therapy aimed at this marker may hold promise in preventing tumor recurrence. Indeed, EpCAM-targeted CAR-T cells have also shown strong antitumor efficacy through recognizing and eliminating EpCAM-positive BCSCs. HER2-directed CAR-T cells are also being investigated in HER2 positive breast cancer settings where BCSCs are known to contribute to therapy resistance. But problems including tumor heterogeneity, antigen escape, and the immunosuppressive tumor microenvironment have been reported to restrict the efficacy of CAR-T therapy in solid tumors such as breast cancer. To address these challenges, researchers are investigating approaches such as dual-target CAR-T cells (CD44/EpCAM or HER2/PD-L1), armed CAR-T cells with cytokine assistance (IL-12, IL-15), and CAR-T cells with immune checkpoint blockade (PD-1 knockout CAR-T cells) to improve persistence and efficacy towards BCSCs.

Immunotherapy with Natural Killer (NK) cells presents another strategy that differs from the CAR-T cell therapy (Figure 2). T cells have a more limited ability to identify and kill tumor cells because they require MHC-dependent recognition. Since BCSCs are resistant to adaptive immunity, NK cells are particularly effective at recognizing and killing them. Cytotoxicity is achieved by NK cells through the release of perforin and granzymes, ADCC, and cytokine production (IFN-γ, TNF-α). CAR-NK cells are genetically engineered to express receptors that recognize BCSC markers such as CD133, EpCAM, or NKG2D ligands to increase their directedness and potency (Maddineni et al., 2022). CAR-NK cells are reported to have reduced likelihood of CRS and GVHD compared to CAR-T cells, which makes them a safer option for BCSC targeted immunotherapy. The source of NK cells for application includes umbilical cord blood and induced Pluripotent Stem Cell (iPSC)-derived NK cells, which are exploitable and universal banked for possible use in the clinic (Albinger et al., 2021).

Figure 2: CAR-T and NK cell therapy in cancer treatment (From the patient or the donor blood, T or NK cells are harvested. Then the cells are genetically engineered to express Chimeric Antigen Receptors (CARs). Expanding CAR-T or CAR-NK cells until there are enough for injection back into the patient, where they can help fight cancer cells) (Saenz-Antoñanzas et al., 2021).

Gene therapy and RNA-based therapies

CRISPR/Cas9 technology has become a tool, in the fight against BCSC targeting genes essential for their survival and ability to resist treatments effectively. Unlike therapies that struggle to eradicate BCSC due to their adaptability and defense mechanisms, CRISPR/Cas9 allows accurate genetic alterations to hinder activities at a molecular level. CRISPR/Cas9 shows potential in targeting cells by disabling important transcription factors like SOX2 and OCT4 that play a crucial role in sustaining the growth and versatility of these cells (MacLean et al., 2024). Preclinical trials have shown that removing SOX2 using CRISPR significantly decreases the ability of cells to initiate tumors and spread them further (Wu et al., 2021). Targeting NANOG and OCT 3/4 has also been demonstrated to trigger the differentiation of BCSCS into tumorigenic cells which increases their susceptibility to conventional treatments (Mohapatra et al., 2022).

One approach involves disrupting communication pathways that control the survival of BCSC such, as the Wnt and Notch pathways along with Hedgehog and PI3K/AKT pathways. Deactivating β CTNNB a crucial player in the Wnt pathway using CRISPR/Cas9 technology causes a decline in growth and tumor development (Martins-Neves et al., 2023). Similarly targeting NOTCH or SMO (for the Hedgehog pathway) lowers stem cell characteristics boosts sensitivity, to chemotherapy treatments (Nagampalli et al., 2025). These gene editing methods offer a means to halt communication routes that support BCSCs survival. CRISPR/Cas9 can also be applied to make BCSC more responsive, to chemotherapy and immunotherapy by deactivating genes that cause drug resistance like ABCB (MDR) which produces P glycoprotein that plays a role in chemoresistance and has been successfully targeted with CRISPR to boost sensitivity to chemotherapy treatments (Saha et al., 2022). Similarly editing PD L expression, in BCSC can help immune cells identify them better and boost the effectiveness of checkpoint inhibitors.

RNA interference (RNAi) is a novel treatment strategy that exploits small RNA molecules to knock down specific genes, which is a better targeted way of attacking BCSCs (Kar et al.,, 2023). BCSCs are responsible for tumor formation, growth, metastasis and treatment resistance; thus, siRNAs and miRNAs have been considered as potential targets in the management of BCSCs. Therefore, RNAi therapy, through selective gene silencing, may be able to address the challenges of current therapies and enhance the overall quality of care for patients.

siRNA-Based Strategies

siRNAs are small double stranded RNA molecules that binds to complementary mRNA leading to degradation of mRNA and inhibition of protein synthesis. In the case of BCSCs, siRNA-based therapies have been developed to knock down genes that are stake holders in stemness, self-renewal, therapy resistance and immune evasion. One important target is SOX2, a transcription factor that is play a crucial role in regulating self-renewal of BCSC. Studies have indicated that SOX2 gene can be turned off through siRNAs, which in turn reduces tumor propagation and increases the tendency of the cells to undergo differentiation, thus making the BCSCs vulnerable to conventional treatment (Serej et al., 2021). Other important transcription factors such as NANOG and OCT4 have also been successfully knocked down with siRNA, which leads to reduced tumorigenicity (Li et al., 2022).

Another promising strategy of siRNA-based therapy is to target signaling pathways that are crucial for the propagation of BCSCs. The Wnt, Notch and Hedgehog pathways are stromal factors that are important for the propagation and therapy resistance of BCSCs. The siRNA mediated depletion of β catenin (CTNNB1) has been found to suppress BCSC proliferation and tumor growth (Kevat et al., 2025; Nogueras Pérez et al., 2023). Likewise, blocking NOTCH1 or JAGGED1 in the Notch pathway reverses the self-renewal ability while inhibiting SMO or GLI1 in the Hedgehog pathway eliminates the stem like properties of BCSCs (Li et al., 2021). and hence can be sensitized to chemotherapy. The efficacy of siRNA therapy in combating chemoresistance in BCSCs has also been investigated. Most of the BCSCs possess the properties of drug efflux pumps such as ABCB1, which transports chemotherapy drugs out of the cells thus decreasing the effectiveness of treatment. By using siRNA to silence the ABCB1 gene, chemosensitivity is reinstated by blocking the efflux of drugs and thus allowing for a more efficient eradication of the BCSCs. In the same manner, knocking down BCL-2, an anti-apoptotic protein increases the rate of apoptosis in BCSCs thus making them sensitive to chemotherapy and radiotherapy.

miRNA-Based Strategies

miRNAs are small, endogenous, non-coding RNAs that translate multiple target mRNAs by inhibiting their translation. In breast cancer, the expression of certain miRNAs is decreased (tumor suppressive miRNAs) or increased (oncogenic miRNAs, also known as oncomiRs) in BCSCs, which in turn affect their proliferation, metastasis and therapy resistance (Cavallari et al., 2021).

Using miRNA mimics to replace lost tumor suppressive miRNAs has the ability to suppress BCSC function. miR-34a is a well-known tumor suppressor that directly targets NOTCH1 and BCL2 to block BCSC self-renewal and induce apoptosis (Ma et al., 2021). The EMT is a key process that allows BCSCs to invade and metastasize, and miR200c is a crucial miRNA in this inhibition. It was reported that ZEB1/2, transcription factors that promote EMT, are suppressed by over expression of miR200c, which in turn reduces the metastatic potential (da Silvia Lima et al., 2024). Another important miRNA, let7, is down regulated in BCSCs and this miRNA targets oncogenes such as HMGA2 and RAS to suppress tumor initiation capacity (Nogueras Pérez et al., 2023).

oncomiRs that support BCSC survival can also be targeted using miRNA inhibitors (antagomiRs). miR21 is one of the most highly expressed oncomiRs in breast cancer and it enhances therapy resistance by repressing tumor suppressors PTEN and PDCD4 (Mir et al., 2024). Using antagomiRs to target miR21 restores PTEN activity, leading to decreased proliferation and increased chemotherapy sensitivity. Similarly, miR155 promotes the BCSC phenotype by activating the PI3K/AKT signaling pathway to increase survival and self-renewal. Reduction of miR155 has been reported to decrease the BCSC population and enhance the efficacy of targeted therapies (Mirchandani et al., 2024).

Nanotechnology-based targeting

One of the most promising strategies to effectively eradicate CSCs is nanoparticle-based drug delivery, which enables the precise, targeted and sustained release of drugs to CSC populations with minimal impact on normal cells (Beach et al., 2024). Nanoparticles have several advantages including increasing the solubility of the drug, increasing the circulation time of the drug, site specific drug delivery and controlled drug release and the ability to cross biological barriers which are otherwise inaccessible to conventional drug delivery systems. The different nanocarrier systems developed to target breast cancer stem cells include lipid-based nanoparticles, polymeric nanoparticles, metallic nanoparticles and extracellular vesicles. Lipid nanoparticles such as liposomes and SLN (solid lipid nanoparticles) have been most commonly used because they are biocompatible and can encapsulate hydrophobic drugs (Tang et al., 2021). Selective targeting of CSCs with liposomes loaded with agents such as doxorubicin, paclitaxel or salinomycin has also been found to be effective. Polymeric nanoparticles such as those prepared from materials like PLGA or chitosan enable the controlled and sustained release of drugs, which reduces the frequency of dosing (Montazersaheb et al., 2023). Metallic nanoparticles including gold, silver and iron oxide nanoparticles have emerged due to their surface properties and potential to use in theranostics (combination of therapy and imaging). Gold nanoparticles conjugated with siRNA or small molecule inhibitors of CSC signaling pathways (Wnt, Notch, Hedgehog, etc.,) has been found to be effective in suppressing CSCs self-renewal (Fatima et al., 2024). Hyperthermia therapy is another potential application of magnetic nanoparticles, especially iron oxide-based formulations, which can be used to induce localized heating to kill BCSCs (Safa et al.,, 2022).

To increase the nanoparticle drug delivery to CSCs specificity, ligand targeting has been considered. CSCs of breast cancer can be distinguished by surface markers including CD44, CD133, EpCAM and ALDH1 (Wu et al., 2021). Antibody or ligand-functionalized nanoparticles selectively accumulate in CSCs through their attachment to these markers. For instance, BCSCs-targeting hyaluronic acid-coated nanoparticles have been created to transport chemotherapeutic agents and small-molecule inhibitors to CSC populations using CD44 ligand, leading to a reduced tumor recurrence (Giuli et al., 2021). In addition, nanoparticles conjugated with anti-EpCAM antibodies have shown promising results in the targeting and elimination of BCSCs in preclinical studies. Stimuli-responsive nanoparticles have also been used which get activated to release the drug in response to change in pH, temperature, enzymes or redox in the tumor environment (Yang et al., 2020). Because CSC niches are usually acidic and hypoxic, pH-sensitive nanoparticles have been created to deliver drugs within CSC-rich areas with less impact on other tissues. Enzyme-responsive nanoparticles that are degraded by tumor-associated proteases also enhance the specificity of drug delivery and reduce the side effects systemically.

Combination strategies with conventional therapies

Chemotherapy and radiation therapy are commonly used to treat breast cancer as the methods of treatment; however, their effectiveness can be limited due, to the presence of BCSC. Breast Cancer Stem Cells which naturally resist these treatments well by having DNA repair mechanisms and high levels of drug transporters that reduce the effects of standard treatments by going into a dormant state as a way to evade them. Bringing together chemotherapy and radiation therapy, with inhibitors that target BCSC has shown promise in improving treatment outcomes and reducing the chances of cancer returning in the future (Table 1).

Table 1: Summary table of chemotherapy and radiotherapy with CSC inhibitors for the treatment of breast cancer.
Therapeutic ApproachCSC InhibitorTargeted PathwayChemotherapy/Radiotherapy AgentMechanism of ActionKey FindingsReferences
Chemotherapy + Notch Inhibitorγ-Secretase Inhibitors (GSIs)Notch SignalingPaclitaxel, DoxorubicinInhibits BCSC self-renewal and sensitizes cells to chemotherapy.Enhanced cytotoxicity & reduced tumor recurrence(Wu et al., 2021).
Chemotherapy + Wnt InhibitorLGK974Wnt/β-Catenin PathwayDoxorubicin, CisplatinBlocks Wnt signaling to prevent BCSC maintenance and enhances chemotherapy response.Increased apoptosis and decreased BCSC population(Babikian et al., 2020).
Chemotherapy + Hedgehog InhibitorVismodegib, SonidegibHedgehog Pathway5-Fluorouracil (5-FU), PaclitaxelSuppresses Hedgehog-driven CSC survival and enhances chemotherapy efficacy.Improved tumor shrinkage and lower recurrence rates(Gounder et al., 2022).
Radiotherapy + Notch InhibitorRO4929097Notch SignalingIonizing RadiationReduces BCSC radioresistance by impairing DNA repair and survival signaling.Enhanced radiosensitivity and tumor control(Maddineni et al., 2022).
Radiotherapy + Wnt InhibitorPRI-724Wnt/β-Catenin PathwayIonizing RadiationDisrupts BCSC stemness and improves radiotherapy response.Increased radiation-induced apoptosis in BCSCs(Maddineni et al., 2022).
Combination Therapy with Dual InhibitorsBortezomib + GSIsNotch & Proteasome PathwayCisplatin, RadiationTargets multiple resistance pathways to eliminate BCSCs.Greater tumor reduction and prolonged survival(Moore et al., 2020).

Chemotherapy is effective, in fighting tumor cells. Sometimes doesn't completely eliminate BCSCs leading to cancer recurrence and spreading to other parts of the body (metastasis). When chemotherapy drugs are given along with inhibitors targeting pathways such as those related to the Notch and Hedgehog genes among others like the Wonder gene (Wnt) there have been noticeable improvements in treatment results observed.

CONCLUSION

Breast cancer stem cell is a crucial target to overcome therapy resistance, metastasis and tumor recurrence. However, while much is now known about BCSC biology, phenomena such as plasticity, tumor heterogeneity, and microenvironmental interactions continue to pose a challenge to treatment efficacy. Combination strategies of chemotherapy, radiotherapy, small molecule inhibitors, immunotherapy, and nanocarrier-based drug delivery seem to hold promise in eradication of both CSCs as well as bulk tumor cells. However, these approaches cannot be simply translated to clinical success, and this needs better preclinical models, biomarker driven therapies and personalized treatment strategies. There is therefore going to be a continued need for research and innovation in the field of CSC targeted therapies in order to obtain durable responses and improve survival rates in breast cancer patients.

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Alam, Q., Alazragi, R. S., Al-Kathiri, A., Albaz, A. A., Alshehri, J. M., Alsaffar, F. A., Alammari, D., & Alqahtani, S. (2026). Cancer Stem Cells in Breast Cancer: Unlocking New Frontiers in Therapeutic Strategies. International Journal of Pharmaceutical Investigation, 16(2), 523–535. https://doi.org/10.5530/ijpi.20260153