A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 2013 and May 2025. The search was conducted using predefined search strings that combined terms related to “chemotherapy resistance,” “hematological malignancies,” and specific cancer types (e.g., AML, lymphoma, MM). The inclusion criteria for the present study encompassed peer-reviewed original research and reviews that reported on the molecular, cellular, or therapeutic aspects of chemotherapy resistance. The exclusion criteria encompassed non-English articles, conference abstracts, and studies with a exclusive focus on solid tumors. Two reviewers independently evaluated titles and abstracts, documented the data in a standardized extraction form, and resolved discrepancies through consensus.

Molecular Pathways of Chemotherapy Resistance

Genetic and Epigenetic Alterations

Gene Mutations and Clonal Heterogeneity

The phenomenon of chemotherapeutic resistance in cancerous cells is significantly influenced by the dynamic clonal evolution of these cells. In this process, early mutations are present across most cancer cells (clonal), while later mutations are confined to subpopulations (subclonal). As Ngu et al. (2022) have demonstrated, relapses frequently occur when chemotherapy fails to eliminate dominant or rare pre-existing resistant subclones. Chemotherapy itself has been shown to act as a selective pressure, driving the expansion of these resistant clones (Ngu et al., 2022).

In the context of Acute Myeloid Leukemia (AML), specific gene mutations have been demonstrated to be significantly associated with resistance. TP53 mutations, for instance, are recognized as poor prognostic markers. These alterations disrupt the DNA damage repair and apoptosis pathways, thereby accelerating the generation and expansion of resistant clones through enhanced genomic instability (Cao et al., 2025). Furthermore, the presence of RAS mutations has been observed to be selected by chemotherapy, particularly in elderly AML patients, contributing to unfavorable outcomes (J. Zhang et al., 2019). FLT3-ITD (FMS-like tyrosine kinase 3-internal tandem duplication) mutations have been identified as critical drivers of disease progression and resistance, often persisting at relapse with an increased allele burden (J. Zhang et al., 2019). Other significant contributors to chemotherapy resistance include KMT2A rearrangements, IDH1/2 mutations (which lead to epigenetic dysregulation), DNMT3A mutations (causing aberrant methylation patterns and transformation into chemotherapy-resistant leukemia stem cells), and ASXL1 mutations (disrupting epigenetic regulation and sustaining undifferentiated leukemia stem cells) (J. Zhang et al., 2019).

In Lymphoma, ongoing somatic hypermutation processes facilitate the acquisition of additional genetic lesions, thereby promoting resistance (Cao et al., 2025). The presence of mutated oncogenes, such as EZH2, CREBBP, MYD88, CD79B, NOTCH1, BCL6, PIM1, and BCL2, in conjunction with chromosomal translocations, including t(14;18) (which juxtaposes BCL2 to the immunoglobulin heavy chain locus, IGHV), has been identified as a contributing factor to the development of aggressive phenotypes and drug resistance (Klener & Klanova, 2020). Furthermore, the inactivation of tumor suppressor genes, including TP53, ATM, CDKN2A, and KMT2D, has been demonstrated to lead to genomic instability, which in turn drives lymphoma evolution and resistance (Klener & Klanova, 2020).

Multiple Myeloma (MM) cells are distinguished by significant genomic abnormalities, including chromosomal instability, various mutations, and microsatellite instability, as well as IgH translocations. These abnormalities accumulate throughout the course of the disease and are central to the development of drug resistance (Gourzones et al., 2019). The activation of oncogenes such as cyclins, FGFR3, and MYC also plays a significant role in MM resistance (Pinto et al., 2020).

MicroRNA (miRNA) Dysregulation

MicroRNAs (miRNAs) are a class of small non-coding RNAs that play a crucial role in regulating gene expression. These molecules influence a variety of processes, including cell division, self-renewal, invasion, and DNA damage response (J. Zhang et al., 2019). Alterations in the expression of microRNAs (miRNAs) have been demonstrated to exert a substantial influence on the upregulation of drug resistance, a process that is facilitated by the impact on DNA damage repair mechanisms. For instance, the over-expression of microRNA-181a in AML cells has been demonstrated to downregulate Ataxia Telangiectasia Mutated (ATM), a DNA damage response protein, resulting in unrepaired DNA damage and drug resistance. In a similar manner, the expression of microRNA-182 has been observed to result in a decrease in Rad51 protein levels, thereby increasing residual DNA damage and reducing cell survival following exposure to DNA-damaging agents (J. Zhang et al., 2019). Furthermore, the function of microRNAs in causing cell cycle arrest has been demonstrated, as evidenced by the study of microRNA-638, which has been shown to inhibit cyclin-dependent kinases (CDK), and their role in the suppression of apoptosis, as illustrated by the observation that low levels of microRNA-181a have been found to downregulate Bcl-2 (J. Zhang et al., 2019). In the context of MM, aberrant expression patterns of miRNAs have been observed during the progression of the disease, with these patterns contributing to resistance (Pinto et al., 2020).

Epigenetic Modifications (DNA Methylation, Histone Modifications)

Aberrant epigenetic changes, which refer to heritable modifications to gene function without altering the DNA sequence itself, have been identified as critical contributors to cancer progression and drug resistance. These include DNA methylation, characterized by both hypermethylation of tumor suppressor gene promoters and global hypomethylation, and histone modifications, particularly an imbalance in acetylation and deacetylation (Eslami et al., 2024). Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have also been identified as pivotal epigenetic regulators, impacting chromatin structure and gene expression (Eslami et al., 2024).

In Multiple Myeloma (MM), hypomethylation of DNA and hypermethylation of tumor suppressor genes result in aberrant gene expression, including the upregulation of ABCG2, which enhances drug efflux (Pinto et al., 2020). Abnormal microRNA expression, such as the upregulation of miR-21 or the downregulation of miR-15a and miR-16, has been shown to further disrupt pathways involved in the pathogenesis and drug resistance of multiple myeloma (Pinto et al., 2020). In lymphomas, epigenetic modifications have been shown to cause alterations in chromatin and DNA methylation, thereby promoting oncogenesis, metastasis, angiogenesis, and drug resistance (Klener & Klanova, 2020).

The intricate relationship between genetic mutations and epigenetic modifications creates a robust resistance phenotype. Genetic mutations, including TP53 deletion, have been demonstrated to exert a direct influence on epigenetic regulators. This influence can be illustrated by the stabilization of BCL2 through the modulation of microRNAs, as reported by Klener and Klanova (2020). In contrast, epigenetic changes, including DNA methylation, have been shown to modify gene expression, resulting in the increased expression of drug efflux pumps (Pinto et al., 2020). This finding suggests the presence of a complex, bidirectional regulatory network in which genetic and epigenetic alterations are not isolated events but rather mutually reinforcing, contributing to a more entrenched resistance. Given the mutual reinforcement between these factors, it is imperative to implement effective strategies that target both genetic mutations and their epigenetic consequences concurrently. This approach is crucial to preemptively halting compensatory resistance pathways.

Altered Drug Transport and Metabolism

Drug Efflux Pumps (ABC Transporters: P-glycoprotein, MRP1, BCRP)

The active extrusion of anticancer drugs by members of the ATP-binding cassette (ABC) transporter family is one of the most widely recognized mechanisms contributing to multidrug resistance (MDR) (Pinto et al., 2020). These transporters, including P-glycoprotein (P-gp, also known as MDR1 or ABCB1), Multidrug Resistance-associated Protein 1 (MRP1 or ABCC1), and Breast Cancer Resistance Protein (BCRP or ABCG2), actively pump a wide range of chemotherapeutic agents out of cancer cells. This action has been demonstrated to reduce intracellular drug concentrations, thereby limiting therapeutic efficacy (Pinto et al., 2020).

The presence of P-gp overexpressions has been demonstrated to be significantly associated with adverse outcomes in patients diagnosed with AML, including elevated white blood cell counts, the presence of chromosomal abnormalities, and a reduced overall survival rate (J. Zhang et al., 2019). Its expression is frequently linked to the activation of critical signaling pathways, such as NF-κB and PI3K/AKT/mTOR (J. Zhang et al., 2019). Furthermore, Lung Resistance Protein (LRP) has been shown to contribute to drug resistance by either blocking nuclear pores or facilitating the transport of drugs via exocytosis (J. Zhang et al., 2019). In multiple myeloma (MM), P-gp overexpression has been observed in resistant cells and is increased after treatment with drugs like vincristine and doxorubicin, predicting MDR and relapse (Pinto et al., 2020).

Drug Inactivation and Detoxification

Enzymes such as Glutathione S-transferases (GSTs), particularly GSTπ, are highly expressed in AML cells and contribute to drug resistance. These enzymes facilitate the detoxification of reactive electrophiles and cytotoxic therapeutic agents by binding them to glutathione, thereby reducing their cytotoxic effects (J. Zhang et al., 2019). In AML, increased expression of UDP-glucuronosyltransferase 1 A (UGT1A) and GLI1 has been observed to induce glucuronidation, a process that results in the inactivation and subsequent elimination of drugs from the body (Talib et al., 2021). Conversely, a reduction in the levels of equilibrative nucleoside transporter 1 (ENT1), which facilitates drug entry into cells, can also lead to resistance (Talib et al., 2021).

The data suggest that cancer cells utilize not only a single, discrete strategy, but rather multiple interconnected mechanisms to restrict intracellular drug concentrations. This includes active efflux via ABC transporters that pump drugs out (J. Zhang et al., 2019), mechanisms that prevent drug entry, such as reduced ENT1 levels (Emran et al., 2022), and enzymatic inactivation processes mediated by enzymes like GSTs and UGT1A (Niu et al., 2022). This multi-layered approach suggests a redundant and highly adaptive system for drug evasion, where if one mechanism is inhibited, others may compensate. Consequently, the successful overcoming of this resistance necessitates a multifaceted approach, which must address diverse aspects of drug transport and metabolism. The efficacy of a single efflux pump inhibitor may be limited if other mechanisms can compensate. Future therapeutic interventions may necessitate the combination of efflux pump inhibitors with strategies designed to enhance drug uptake or inhibit detoxification enzymes to achieve more comprehensive and durable responses.

Leukemia/Cancer Stem Cells (LSCs/CSCs)

Leukemia Stem Cells (LSCs) and cancer stem cells (CSCs) represent a small, distinct population within the tumor that possesses unique properties, including self-renewal capabilities, quiescent cell cycle characteristics, and intrinsic drug resistance. These characteristics render them a significant contributor to the occurrence of relapse and treatment failure in hematological malignancies (Pinto et al., 2020). These cells have demonstrated a high degree of resilience, capable of surviving conventional chemotherapy regimens that effectively eliminate the majority of tumor cells. However, subsequent repopulation of the malignancy by these cells often results in disease recurrence (Cao et al., 2025).

Quiescence and Self-Renewal Properties

LSCs and CSCs frequently exist in a quiescent or non-proliferative (G0) state. This dormancy confers a substantial protective benefit against cell cycle-specific chemotherapeutic agents, which predominantly target rapidly dividing cells (Pinto et al., 2020).

Drug Efflux Capacity in LSCs/CSCs

A critical mechanism of resistance in LSCs and CSCs is their augmented capacity for drug efflux. It has been observed that these cells frequently overexpress various ABC transporters, including ABCB1, ABCA3, and ABCG2. This enables them to rapidly expel chemotherapeutic agents from within the cell. This active expulsion mechanism has been demonstrated to contribute significantly to their intrinsic drug resistance (Pinto et al., 2020).

Metabolic Reprogramming in LSCs/CSCs

LSCs and CSCs manifest disparate metabolic profiles that contribute to their drug resistance. In contrast to mature, glycolysis-dependent AML blasts, quiescent LSCs frequently depend on mitochondrial oxidative phosphorylation (OXPHOS) and maintain low levels of reactive oxygen species (ROS), which enhance their resistance to chemotherapy (Cao et al., 2025). At the time of relapse, LSCs may undergo further metabolic shifts, such as transitioning to fatty acid metabolism to compensate for OXPHOS and meet their energy demands (Cao et al., 2025). In multiple myeloma (MM), cancer stem cells (CSCs) exhibit elevated activity in oxidative phosphorylation (OXPHOS), the serine synthesis pathway (SSP), and the tricarboxylic acid (TCA) cycle (Pathak et al., 2023). In a similar manner, lymphoma cells are distinguished by their elevated glucose uptake, deregulated glycolysis, and increased glutamine and fatty acid synthesis. These characteristics contribute to their survival and resistance (Pathak et al., 2023).

The consistent identification of LSCs and CSCs as primary drivers of relapse highlights their critical role in chemotherapy resistance. Their inherent resistance mechanisms, such as quiescence and drug efflux, coupled with their ability to repopulate the tumor, highlight their critical contribution to treatment failure (Cao et al., 2025). The concept of “primary” and “secondary” resistance mechanisms in acute myeloid leukemia (AML), wherein LSCs can intrinsically resist or reacquire stemness under therapeutic pressure (Niu et al., 2022), further illustrates their dynamic and adaptive nature. Their metabolic adaptability — shifting from glycolysis to OXPHOS or fatty acid metabolism (Cao et al., 2025) indicates that their resistance phenotype is not static. Thus, achieving effective long-term remission requires eliminating not just the bulk tumor but also specifically targeting and eradicating these LSCs and CSCs. Targeting LSCs/CSCs requires therapies that disrupt dormancy and exploit metabolic vulnerabilities because these cells evade conventional cytotoxic regimens. Metabolic dependencies, such as OXPHOS reliance, have been identified in resistant stem cell populations; however, the strength of clinical evidence remains limited, as most studies are small-scale or exploratory. Future studies should prioritize longitudinal metabolic profiling in patient cohorts to validate these targets and determine their therapeutic exploitability. 

Evasion of Apoptosis and Cell Death

Intrinsic or acquired resistance to apoptosis (programmed cell death) is a hallmark of human cancers and a major cause of treatment resistance (Pinto et al., 2020). This is significant because most current anticancer therapies function by activating cell death pathways, including apoptosis, in cancer cells (Castro-Muñoz et al., 2023).

Dysregulation of Apoptotic Pathways (Bcl-2 Family, NF-κB)

The Bcl-2 family of proteins includes both pro-apoptotic members, such as BAX and BAK, and anti-apoptotic members, including Bcl-2, Bcl-xL, and Mcl-1. These proteins are key regulators of the intrinsic apoptotic pathway. Overexpression of anti-apoptotic Bcl-2 proteins is often seen in hematologic malignancies and contributes directly to both chemotherapy and radioresistance (Pinto et al., 2020).

The nuclear factor kappa B (NF-κB) pathway also plays a crucial role by mediating the expression of multiple genes involved in cell proliferation and anti-apoptosis. Constitutive activation of NF-κB is common in multiple myeloma (MM), and drug-sensitive MM cells typically exhibit lower NF-κB activity than their resistant counterparts (Pinto et al., 2020). Additionally, the PI3K/AKT signaling pathway is a critical pro-survival pathway that promotes cell growth, proliferation, and invasion while inhibiting apoptosis. This makes it a significant target for antitumor drugs (Pinto et al., 2020).

Autophagy Activation

Autophagy is a cellular process involving self-phagocytosis and the recycling of cellular components that can be induced by chemotherapeutic drugs. It is a significant factor in tumor cells developing drug resistance (Pinto et al., 2020). Autophagy can contribute directly to drug resistance by reducing intracellular drug concentrations and preventing apoptosis via a protective mechanism (J. Zhang et al., 2019). For instance, hypoxia-induced autophagy has been demonstrated to decrease chemosensitivity in T-cell lymphomas (Klener & Klanova, 2020).

Evasion of apoptosis is achieved through a complex interplay of dysregulated pro-survival pathways and adaptive cellular processes, not a single mechanism. Simultaneous activation of multiple anti-apoptotic pathways—such as overexpression of Bcl-2 family proteins, constitutive activation of NF-κB, and PI3K/AKT signaling dysregulation—combined with protective autophagy activation suggests cancer cells have multiple “escape routes” from drug-induced death. This indicates that therapies targeting apoptosis must consider this redundancy and the potential for compensatory mechanisms. Consequently, single-agent pro-apoptotic drugs might be insufficient if multiple anti-apoptotic pathways are active or if autophagy provides a survival advantage. Combination therapies that simultaneously inhibit multiple pro-survival pathways or block protective autophagy are likely to be more effective in overcoming this fundamental hallmark of drug resistance.

Enhanced DNA Damage Response and Repair

Chemotherapeutic drugs often induce DNA damage, particularly double-strand breaks (DSBs), to trigger cell death (Denizot et al., 2022). Resistance to these agents can occur through mechanisms that suppress the accumulation of DSBs or enhance their repair (Talib et al., 2021). Cancer cells often have alterations in their DNA repair pathways, which contribute to their genomic instability and subsequent resistance (Fletcher et al., 2016).

DNA Repair Pathways (HR, NHEJ, NER, BER, MMR)

The two main pathways for repairing DNA double-strand breaks (DSBs) are homologous recombination (HR) and nonhomologous end joining (NHEJ) (Fletcher et al., 2016). Defects in HR, such as BRCA1/2 mutations, initially sensitize cancers to DNA-damaging agents. However, the reactivation of HR repair is a major mechanism of acquired resistance (Álvarez-Carrasco et al., 2025). Elevated NHEJ activity and the overexpression of its components also contribute to chemoresistance. Nucleotide excision repair (NER) is crucial for resolving cisplatin-induced intrastrand DNA crosslinks, and NER inactivation can increase drug sensitivity (Niu et al., 2022). Base excision repair (BER) and mismatch repair (MMR) also play roles in the DNA damage response. Loss of MMR can sometimes drive resistance (Mazewski & Platanias, 2023).

Replication Stress Tolerance Mechanisms

Many chemotherapeutic agents interfere with DNA replication. To counteract this, cancer cells activate various replication stress response mechanisms, such as translesion synthesis (TLS), template switching (TS), fork reversal, and repriming. These mechanisms enable cells to repair DNA lesions and prevent the formation of lethal double-strand breaks (DSBs), thereby contributing to drug resistance (Choi et al., 2024).

Specific to Hematological Cancers

In Chronic Lymphocytic Leukemia (CLL), the ability of CLL cells to efficiently repair alkylator-induced DNA damage explains their poor response to certain chemotherapies (Phi et al., 2018). Mutations in genes such as TP53, ATM, CHEK1/2, POT1, BRCA1, and CHD2 have been identified. The ATM-Chk2-p53 signaling axis plays a critical role in the apoptotic response to DNA damage (Jung & McCarty, 2010). ATM mutant cells, in particular, exhibit impaired DSB repair (Roszkowska, 2024).

In Lymphoma, Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) exhibit genetic instability and an abnormal DNA damage response and repair process (Solimando et al., 2022). Studies have shown that inhibiting DNA repair mechanisms using small molecules (e.g., ATR, CHK1, and Wee1 inhibitors) can induce apoptosis and inhibit proliferation in cHL cell lines (X. Chen et al., 2020). In non-Hodgkin lymphoma (NHL), an increase in DNA repair machinery can decrease drug efficacy. Aberrations in TP53, ATM, and CDKN2A are linked to resistance (Matamala Montoya et al., 2023).

Despite their slow proliferation rate, Multiple Myeloma (MM) cells exhibit extensive genomic rearrangements and intense genomic instability. They depend on robust DNA repair mechanisms to survive damage induced by chemotherapy (Matamala Montoya et al., 2023). Although mutations in DNA damage response (DDR) genes, such as ATM and ATR, are uncommon in MM, oncogenes like MYC and RAS can induce intense replicative stress, underscoring the significance of DNA damage in MM pathogenesis (Matamala Montoya et al., 2023).

The data reveal a paradox: cancer cells exhibit genomic instability yet rely on robust DNA repair mechanisms to survive damage caused by chemotherapy (Yu et al., 2022). This indicates that DNA repair is essential for cancer cell survival and represents a vulnerability that can be exploited therapeutically. This concept is known as “synthetic lethality,” which occurs when inhibiting a specific repair pathway in cells already deficient in another pathway leads to selective cell death (J. Li et al., 2025). Thus, targeting DNA repair pathways is a promising therapeutic strategy. By inhibiting specific repair mechanisms, especially those that compensate for existing defects or are upregulated in resistant cells, clinicians can push cancer cells beyond their “tolerance limit” for DNA damage. This makes them more susceptible to conventional chemotherapy or induces cell death directly. This also underscores the importance of identifying specific DNA repair deficiencies in individual tumors to guide personalized treatment strategies. These molecular alterations often act in concert with extrinsic factors, such as the tumor microenvironment. For instance, TP53 or ATM mutations can disrupt DNA repair and modulate stromal signaling, thereby reinforcing resistance phenotypes.

Tumor Microenvironment (TME) and Stromal Support

The tumor microenvironment (TME) is a complex, dynamic ecosystem consisting of cancer cells and various stromal cells, such as fibroblasts, mesenchymal stem cells, endothelial cells, and immune cells. It also includes the extracellular matrix (ECM) and soluble factors, including cytokines and growth factors (Hsiao et al., 2025). The TME is not a passive bystander; it actively promotes tumor growth, survival, and drug resistance. It provides a “safe haven” for cancer cells, especially leukemia/cancer stem cells (LSCs/CSCs) (Cao et al., 2025). Much of the evidence on stromal-mediated resistance in hematological malignancies comes from preclinical or in vitro co-culture models, which may not fully replicate the complexity of patient tumors. Translating these findings into clinical practice will require well-designed trials that quantify the extent to which TME-targeting strategies improve patient outcomes.

Cell Adhesion-Mediated Drug Resistance (CAM-DR)

Direct interactions between tumor cells and stromal cells or the extracellular matrix (ECM) significantly contribute to drug resistance (Pang et al., 2023). In multiple myeloma (MM), MM cells adhere to the ECM and bone marrow stromal cells (BMSCs) via adhesion molecules, including VLA-4, LFA-1, ICAM1, and VCAM1. This adhesion can induce MM cells to produce cell cycle inhibitors, anti-apoptotic proteins (including members of the Bcl-2 family), and ABC drug transporters, thereby promoting drug resistance (Pinto et al., 2020). In acute lymphoblastic leukemia (ALL), culturing ALL cells with mesenchymal stem cells (MSCs) induces hERG1 channel expression on lymphoblast plasma membranes. This activates prosurvival signaling pathways, leading to drug resistance (Yu et al., 2022). Similarly, mantle cell lymphoma-initiating cells (MCL-ICs) exhibit resistance largely due to their quiescent properties and enriched ABC drug transporters (Jung & McCarty, 2010).

Soluble Factor-Mediated Drug Resistance (SFM-DR)

Cytokines and growth factors, such as interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), stromal cell-derived factor-1 alpha (SDF-1α), and hepatocyte growth factor (HGF), are secreted within the tumor microenvironment (TME). These factors provide crucial survival and proliferative signals to tumor cells (Pinto et al., 2020). For instance, IL-6 is known to activate the JAK/STAT3 and PI3K/AKT pathways, which are central to cell survival. AML cells can actively reprogram mesenchymal stromal cells (MSCs) within their niche to increase the expression of IL-6, CCL2, and VCAM-1, further promoting AML cell survival and chemoresistance (Cao et al., 2025). In lymphoma, IL-6 has been associated with acquired resistance to PI3K inhibitors (Klener & Klanova, 2020).

Role of Specific Stromal Cells (MSCs, Osteoclasts, Fibroblasts)

Mesenchymal stem cells (MSCs) play a critical role in protecting leukemia cells from drug-induced apoptosis and supporting leukemia stem cell (LSC) survival. This is partly achieved by increasing oxidative phosphorylation (OXPHOS) and the tricarboxylic acid (TCA) cycle in these cells (Cao et al., 2025). Myeloma-specific inflammatory MSCs create an environment that fosters tumor cell proliferation and recruits and modulates immune cells (Solimando et al., 2022).

In multiple myeloma (MM), osteoclasts and osteoblasts are key components of the bone marrow microenvironment. MM induces bone lysis; in turn, osteoclasts secrete factors that support MM cell survival and progression (Pinto et al., 2020). Concurrently, MM cells inhibit osteoblasts, further contributing to bone disease and creating a vicious cycle that enhances resistance (Solimando et al., 2022).

Cancer-associated fibroblasts (CAFs) secrete pro-tumorigenic factors, contribute to fibrosis within the tumor microenvironment (TME) (which can impede drug penetration), and can transfer exosomes containing microRNAs (miRNAs) that promote chemoresistance and metastasis (Fulda, 2010).

Various immune cells within the TME, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), contribute to an immunosuppressive environment. This suppresses anti-tumor immune responses and actively promotes drug resistance (Klener & Klanova, 2020).

Hypoxia and its Influence on Resistance

Hypoxia, or insufficient oxygen supply, is a common feature of rapidly growing tumors. This low-oxygen environment promotes a more aggressive phenotype and enhances chemoresistance (Klener & Klanova, 2020). Hypoxia-inducible factor 1 alpha (HIF-1α) is a crucial mediator of tumor cell response to therapy under hypoxic conditions. HIF-1α can upregulate ABC transporters, increasing drug efflux; reduce DNA damage in cancer cells; accommodate cancer stem cells; and promote immunosuppression (Emran et al., 2022). HIF-1α also maintains quiescence in LSCs (Choi et al., 2024) and leads to acidosis within the TME. This acidosis inhibits host immune functions and reduces the activity of several chemotherapeutic agents (Klener & Klanova, 2020). Furthermore, hypoxia can induce autophagy, contributing to multidrug resistance.

Exosomes

Exosomes are small vesicles secreted by cells that facilitate intercellular communication within the tumor microenvironment (TME). They transport molecules such as growth factors, cytokines, and microRNAs (miRNAs), which promote tumorigenesis and contribute to drug resistance (Emran et al., 2022).

The TME is an active, dynamic entity that profoundly influences drug resistance through a complex interplay of physical barriers, chemical signals, and cellular interactions (Wei & Konopleva, 2023). The dense extracellular matrix and chaotic vasculature can create physical impediments to drug penetration (Emran et al., 2022). Soluble factors and direct cell-to-cell contact provide pro-survival signals that counteract drug efficacy. TME can also induce metabolic changes in cancer cells that favor resistance and protect LSCs/CSCs from therapeutic agents (Solimando et al., 2022; Cao et al., 2025). This complex microenvironment fosters survival and resistance, indicating that disrupting stromal support and immune suppression is essential for durable responses.