Recent advancements in oncology and biology, along with the emergence of innovative techniques such as next-generation sequencing, have enhanced understanding of cancer initiation and development. Cancer is no longer viewed merely as an abnormal growth of cells but also as a complex disease characterized by dynamic genomic alterations that drive its advancement (Baker et al., 2024; Krupina et al., 2024; Landa and Cabanillas, 2024; MacConaill and Garraway, 2010). The development and progression of cancer can disrupt normal biological functions by invading nearby tissues and spreading to distant organs through metastasis. Various types of therapies have been developed for cancer treatment, including chemotherapy, immunotherapy, and targeted treatments (Goldenberg, 1999; Gu et al., 2025; Xie et al., 2024; Xu et al., 2025). However, chemotherapy remains the primary treatment for many cancers, and achieving complete eradication of tumor cells is often difficult due to resistance observed in tumors (Chen et al., 2024; Dong et al., 2024; Ji et al., 2024; Longley and Johnston, 2005; Miao et al., 2025; Teng et al., 2024). Therefore, it is crucial to develop innovative strategies for addressing chemoresistance in cancer (Abdullah and Chow, 2013). Among the various factors, focusing on the roles of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) in tumor progression can enhance our understanding of chemoresistance and improve treatment options through therapeutic advancements.

Resistance to cancer drugs remains a major challenge in oncology, significantly reducing the efficacy of chemotherapy (Gottesman, 2002; Housman et al., 2014; Russo et al., 2024; Vasan et al., 2019; Wang et al., 2019; Zheng et al., 2024). Resistance mechanisms are diverse and include genetic mutations(Rueff and Rodrigues, 2016), epigenetic alterations(Adhikari et al., 2022; Wang et al., 2023), and adaptive modifications in tumor cells. Key factors contributing to resistance are the activation of drug efflux pumps (Robey et al., 2018), increased DNA repair processes (Chen et al., 2024; Fink et al., 1998; Salehan and Morse, 2013), and the upregulation of survival signaling pathways. Moreover, CSCs(Nunes et al., 2018), which inherently resist treatments, and the EMT process, which endows cancer cells with invasive and stem-like characteristics, further intensify resistance (Dart, 2023). The tumor microenvironment (TME), which includes stromal cells, immune cells, and extracellular matrix components, plays a crucial role in forming protective niches and facilitating immune evasion (Kim and Cho, 2022; Samadi et al., 2016; Wang et al., 2020). Combating drug resistance requires a comprehensive approach, incorporating the development of specific therapies targeting resistance mechanisms, combination therapies to address tumor heterogeneity, and strategies to disrupt the supportive tumor microenvironment. Advances in understanding the molecular underpinnings of resistance are vital for creating more effective and tailored cancer treatments. Recent research has greatly enhanced understanding of the mechanisms behind chemoresistance (Chakraborty et al., 2017; Jin et al., 2003; Rice et al., 2017; Su et al., 2023; Taylor-Weiner et al., 2016; Villanueva, 2012; Wang et al., 2014; Zhong et al., 2024). Resistance to drugs has been recorded in numerous tumor types, including ovarian (Hsu et al., 2015; Kim et al., 2018), prostate (Masone, 2023), lung (Bi et al., 2024), glioblastoma (Maciaczyk et al., 2017), lymphoma (Schmitt et al., 2000), breast (Cazet et al., 2018), and pancreatic cancer (Wang et al., 2011), among others.

Several factors can contribute to the clinical resistance, including insufficient intracellular drug levels at the tumor site, the drug’s failure to achieve its optimal pharmacokinetic profile, alterations to the therapeutic target, or differences in the drug’s distribution, metabolism, excretion, or absorption (Alfarouk et al., 2015). For example, taxanes and anthracyclines are frequently used in the treatment of breast cancer. For these drugs to be effective, they must bind to their specific targets: β-tubulin for taxanes and topoisomerase II (topo-II) for anthracyclines. Taxanes bind to β-tubulin, resulting in mitotic arrest and cell death, while anthracyclines interact with topo-II, inducing apoptosis in breast cancer cells. The tumor’s sensitivity to these drugs is primarily influenced by the expression levels and localization of these targets. Moreover, ATP-binding cassette (ABC) transporter proteins like MRP1 facilitate drug resistance by extruding anthracyclines and taxanes from their target sites, thereby reducing intracellular drug levels. More information on chemoresistance can be found in these studies (Moulder, 2010, Ramos et al., 2021).

Chemotherapy drugs target rapidly dividing cells and interfere with crucial DNA functions. These drugs typically induce cell death either by directly damaging DNA or by inhibiting essential processes required for DNA replication and repair. However, a significant challenge in cancer therapy is the development of drug resistance, which gradually diminishes the effectiveness of these treatments. Multiple factors contribute to resistance, including modified DNA repair mechanisms, drug efflux, mutations in therapeutic targets, evasion of apoptosis, and changes in the tumor microenvironment. Additionally, the administration of chemotherapeutic agents may inadvertently promote the expansion of resistant cancer cell populations (Yeldag et al., 2018).

Approaches to address drug resistance include a range of methods, as detailed in various studies (Bu et al., 2010; Dong and Mumper, 2010; Gao et al., 2012; Hu and Zhang, 2012; Montesinos et al., 2012; Nobili et al., 2012). These approaches consist of: a) Modifying chemotherapy protocols to use non-cross-resistant combinations of various active drugs at safe and optimal doses; b) Targeting and inhibiting mRNAs associated with multidrug resistance (MDR) via silencing or degradation methods; c) using monoclonal antibodies directed at extracellular epitopes of MDR efflux transporters, such as P-glycoprotein, which is frequently overexpressed on certain multidrug-resistant cancer cell membranes; d) Developing new chemotherapeutic agents that can avoid being recognized as substrates by MDR efflux pumps; e) Employing small molecule inhibitors of the ABC superfamily of MDR efflux transporters, often referred to as MDR chemosensitizers or modulators; f) Creating targeted nanomedicine strategies that evade MDR pumps, such as increasing drug entry into tumor cells through endocytosis; and g) Combining two or more of the previously mentioned approaches. In recent years, many therapeutic strategies using nanoparticles (NPs) have been developed to combat drug resistance by inhibiting, bypassing, or exploiting different drug efflux pumps and other resistance mechanisms. This rapidly evolving field, which offers innovative and promising approaches to address chemoresistance, was thoroughly analyzed in 2011 (Shapira et al., 2011) and in subsequent publications (Bu et al., 2010; Dong and Mumper, 2010; Z. Gao et al., 2012; Hu and Zhang, 2012; Livney and Assaraf, 2013; Montesinos et al., 2012; Parhi et al., 2012; Xia and Smith, 2012; Zhang et al., 2010).

This review explores the dual roles of EMT and CSCs in promoting resistance to therapy and metastasis in cancer. It examines how these mechanisms, governed by intricate signaling pathways, contribute to tumor progression and therapy resistance. Furthermore, it emphasizes the significance of the TME in promoting these processes through factors such as hypoxia, immune evasion, and stromal interactions.