Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Temozolomide (TMZ), the standard first-line chemotherapy drug is limited by severe toxicity and the development of drug resistance.

To explore the potential of Chuanxiong Rhizoma (CR), a traditional Chinese medicine, in enhancing the efficacy of TMZ against GBM, especially in TMZ-resistant cells under hypoxic conditions.

This study combines in vitro experiments, network pharmacology modeling, molecular docking, and in vivo validation to explore how the essential oil from the blood-activating and stasis-removing Chinese medicine CR (CEO) ameliorate the hypoxic tumor microenvironment and synergizes with TMZ to treat GBM METHODS: The impact of CEO combined with TMZ on the growth, migration, invasion, and apoptosis of glioma U251 cells, including TMZ-resistant variants, was assessed in vitro under both normoxic and hypoxic conditions. Network pharmacology was applied to predict the biological processes and signaling pathways affected by CEO. Western blot analysis was conducted to evaluate the expression of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor A (VEGFA). In vivo, the efficacy of Ligustilide (LIG), a key component of CEO, was tested in combination with TMZ using a mouse model of GBM.

In vitro experiments revealed that the combination of CEO and TMZ significantly inhibited cell growth, migration, and invasion, and induced apoptosis in both TMZ-resistant and non-resistant U251 cells under hypoxic conditions. Network pharmacology suggested that CEO's effects are closely linked to oxygen-related biological processes, with the HIF-1 signaling pathway being a key target. Western blot confirmed that CEO downregulated the expression of HIF-1α, MMP-9, and VEGFA. This suggests that CEO can regulate the expression of these proteins through the HIF-1 signaling pathway, alleviating the TMZ resistance caused by the tumor microenvironment and thereby enhancing the sensitivity of glioma cells to TMZ. In vivo, LIG synergized with TMZ to inhibit tumor growth and enhance the sensitivity of TMZ-resistant GBM.

Our findings indicate that the combination of CEO and TMZ is a promising therapeutic strategy for GBM, particularly in overcoming TMZ resistance.

The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of β-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound K27 significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC50 = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The in vitro studies indicated that compound K27 distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound K27 was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound K27 and PTX exhibited potent tumor suppression in vivo without generating toxicity. These results demonstrated that β-carboline compounds represented by compound K27 may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.

Single-cell transcriptomics has transformed our understanding of cellular diversity, yet noise from technical artifacts and low-quality cells can obscure key biological signals. A common practice is filtering out cells with a high percentage of mitochondrial RNA counts (pctMT), typically indicative of cell death. However, commonly used filtering thresholds, primarily derived from studies on healthy tissues, may be overly stringent for malignant cells, which often naturally exhibit higher baseline mitochondrial gene expression.

We examine nine public single-cell RNA-seq datasets from various cancers, including 441,445 cells from 134 patients, and public spatial transcriptomics data, assessing the viability of malignant cells with high pctMT. Our analysis reveals that malignant cells exhibit significantly higher pctMT than nonmalignant cells, without a notable increase in dissociation-induced stress scores. Malignant cells with high pctMT show metabolic dysregulation, including increased xenobiotic metabolism, relevant to therapeutic response. Analysis of pctMT in cancer cell lines further reveals links to drug resistance. We also observe associations between pctMT and malignant cell transcriptional heterogeneity, as well as patient clinical features.

This study provides insights into the functional characteristics of malignant cells with elevated pctMT, challenging current quality control practices in tumor single-cell RNA-seq analyses and offering potential improvements in data interpretation for future cancer studies.

Phospholipids, complex lipids prevalent in the human body, play crucial roles in various pathophysiological processes. Beyond their synthesis and degradation, phospholipids can influence chemoresistance by participating in ferroptosis. Extensive evidence highlights the significant link between tumor drug resistance and phospholipids. Therefore, drugs targeting phospholipid metabolism itself or the synthesis of corresponding composite materials will effectively overcome the difficulties of clinical tumor treatment.

The imidazoquinoline family of toll-like receptor (TLR) immune cell agonists has long demonstrated moderate anticancer immunogenic effects by activating tumoricidal immune cells and depleting immunosuppressive cells within the tumor microenvironment. At a molecular level, we have also established that several imidazoquinolines traffic from within cancer cells to the extracellular space via P-glycoprotein (P-gp)-mediated efflux, a process commonly upregulated as multidrug-resistant (MDR) cancers acquire chemoresistance. However, imidazoquinoline P-gp efflux has never been deliberately enhanced to exploit this process. This study pioneers efforts to optimize imidazoquinoline efflux, ultimately balancing immunogenic potency alongside functional efflux susceptibility. Starting from an established imidazoquinoline scaffold previously optimized for potency, efflux was significantly enhanced by elaborating the N1 benzylic position with amide- and sulfonamide-linked P-gp affinity fragments consisting of empirically established P-gp substrates as well as computationally predicted P-gp binders. Lead compounds were identified from this series that exhibited enhanced P-gp efflux with functional retention of TLR agonism. Similar to the parent imidazoquinoline scaffold, leads had limited direct cytotoxicity in both treatment-naive and MDR B16 melanoma models and did not significantly affect the efficacy or trafficking of the chemotherapeutic doxorubicin. Efflux-enhanced imidazoquinolines were preferentially expelled from MDR-B16 cells relative to treatment-naive cells, resulting in immunogenicity that was enhanced as a consequence of the acquired MDR phenotype. Because enhanced P-gp-mediated efflux is common to most MDR cancer types, we envision that these results could inspire the design of immunotherapeutic drugs with mechanisms of action that are broadly enhanced in MDR cancers that have failed treatment or acquired resistance to chemotherapeutics.

Flavopiridol, a synthetic flavonoid derived from rohitukine, stands out as a powerful cyclin-dependent kinase (CDK) inhibitor with significant anticancer properties. Its action mechanisms involve inducing cell cycle arrest, triggering apoptosis, and inhibiting transcription across various cancer types. Despite these promising effects, flavopiridol's clinical use has been hampered by issues related to toxicity and drug resistance. This study aims to comprehensively review flavopiridol's mechanisms of action, structure-activity relationships, synthetic derivatives, pharmacokinetics, and its potential role in clinical applications, with a focus on how combination therapies can enhance its efficacy and address resistance challenges in cancer treatment. A thorough analysis of key studies was performed, examining flavopiridol's anticancer properties, emphasizing its structure-activity relationships, synthetic modifications, and clinical outcomes. The anticancer effects of flavopiridol are primarily driven by its inhibition of CDKs, induction of apoptosis, promotion of oxidative stress, and antiangiogenic activity. Modifications in its chemical structure, especially in the D ring, have shown a significant impact on its CDK inhibitory potency. Several synthetic derivatives have also demonstrated enhanced anticancer activity. While preclinical models highlight flavopiridol's potential in treating cancers such as leukemia and solid tumors, clinical trials have brought attention to its limitations, particularly regarding toxicity and resistance. However, flavopiridol remains a promising candidate for cancer therapy, especially when used in combination with other treatments. Future research efforts should focus on refining its therapeutic profile, minimizing toxicity, and investigating synergistic treatment combinations, including those with immunotherapy. Understanding the mechanisms of resistance and discovering predictive biomarkers will be crucial for its effective integration into clinical practice.

The multidrug transporter P-glycoprotein (P-gp), is pivotal in exporting various chemically dissimilar amphipathic compounds including anti-cancer drugs, thus causing multidrug resistance during cancer treatment. P-gp is composed of two transmembrane domains (TMDs), each containing six homologous transmembrane helices (TMHs). Among these helices, TMH 6 and 12 align oppositely, lining a drug-binding pocket in the transmembrane region which acts as a pathway for drug efflux. Previously, we demonstrated that specific mutations within TMH 6 and 12 resulted in loss of substrate efflux and altered the transport direction from efflux to uptake for some substrates. This suggested the presence of a regulatory switch that governs the direction of transport. In this study, we sought to elucidate the mechanism of switch region modulation of the uptake function by engineering several mutants via substituting specific residues in TMH 6 and 12. We discovered that the alanine substitution of four residues (V974, L975, V977, and F978) within the upper region of TMH 12, along with three residues (V334, F336, and F343) within TMH 6, was sufficient to convert P-gp from an efflux to an uptake pump. Additional mutagenesis of the residues in the middle region of TMH 12 revealed that the uptake function, like efflux, is reversible. Further studies, including molecular dynamics simulations, revealed that the switch region appears to act during the substrate translocation step. We propose that the switch region in TMH 6 and 12, which modulates the direction of transport by P-gp, provides a novel approach to selectively target P-gp-expressing cancer cells.

PIM-1 is a type of serine/threonine kinase that plays a crucial role in controlling several vital processes, including proliferation and apoptosis. New synthetic S-amide tetrahydropyrimidinone derivatives were designed and synthesized as PIM-1 inhibitors with potential anticancer activity. Several biochemical assays were performed for anticancer assessment, including PIM-1 inhibitory assays, MTT, apoptosis and cell cycle, gene expression analysis, c-MYC analysis, and ATPase inhibitory assays. Compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibited strong in vitro broad antiproliferative activity against MCF-7, DU-145, and PC-3, with a relatively higher SI index suggesting minimal cytotoxicity to normal cells. Furthermore, these compounds induced mixed late apoptosis and necrosis with cell cycle arrest at the G2/M phase. Moreover, compounds 8b, 8f, 8g, 8k, and 8l showed potent inhibitory action against PIM-1 kinase, with corresponding IC50 values of 660, 909, 373, 518, and 501 nM. In silico prediction studies of physiochemical properties, molecular dynamics, and induced fit docking studies were performed for these compounds to explain their potent biological activity. In conclusion, new pyrimidinone compounds (8c, 8d, 8g, 8h, 8k, and 8l) exhibit potential PIM-1 inhibitory activity and can be used as promising scaffolds for further optimization of new leads with selective PIM-inhibitors and anticancer activity.

Anthocyanins (ACNs) from dark sweet cherries (DSCs) have shown efficacy against breast cancer (BC) cells, particularly triple-negative breast cancer (TNBC) cells, without affecting normal breast cells. This study investigated the impact of ACNs on TNBC cells, focusing on drug resistance mechanisms involving drug metabolism and transport enzymes. Specifically, it was examined whether ACNs influenced Doxorubicin (DOX) metabolism by targeting drug metabolism enzymes (phase I metabolism) and drug transport enzymes (phase III metabolism) in TNBC cells. 4T1 TNBC cells were treated with ACNs, DOX, and the combination of both (ACN-DOX). Results showed a synergistic inhibition of cell viability by ACNs and DOX. In addition, the modulation of phase I drug-metabolizing enzymes was exerted by ACNs, reducing the activity of cytochrome P450 (CYP) enzymes induced by DOX. A reduction of drug efflux by ACNs was shown by decreasing P-glycoprotein (P-gp) activity, leading to a higher intracellular accumulation of DOX. These effects were confirmed using CYP and P-gp inducers and inhibitors, showing their impact on cell viability. In conclusion, the combination of ACNs with DOX has the potential to lower DOX doses, enhance its efficacy, and possibly reduce side effects, offering a promising approach for TNBC treatment.

BackgroundAlzheimer's disease (AD) is a chronic brain degenerative disease that leads to dementia.ObjectiveThe aim of the present study is to investigate the neuroprotective impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) (empagliflozin and dapagliflozin) on tau phosphorylation, oxidative stress, and neuroinflammation.MethodsWe used MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, annexin-V-FITC kit, and DCFH-DA (dichloro-dihydro-fluorescein diacetate) to respectively evaluate the effect of the SGLT2i (empagliflozin and dapagliflozin) on amyloid-β (Aβ)1-42-induced neuronal death, apoptosis, and oxidative stress. The expression of NLRP3-inflammasome, phospho-Tau181, glycogen synthase kinase-3 beta (GSK-3β), cyclin-dependent kinase 5 (CdK5), and histone deacetylase 6 (HDAC6), was quantified by flow cytometry. Drug distribution in the mice's brains was assessed by liquid chromatography-mass spectrometry (LC-MS).ResultsAβ1-42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins. SGLT2i significantly reduced Aβ1-42-induced reactive oxygen species generation, downregulated NLRP3-inflammasome, and diminished tau pathology. Mechanistically, the last effect involved the modulation of GSK-3β and CdK5 protein expression. However, the tested treatments did not modify the Aβ1-42-stimulating effect of HDAC6. Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution.ConclusionsSGLT2i empagliflozin and dapagliflozin exhibited neuroprotective actions against human Aβ1-42-induced neurotoxicity.

Apigenin, a widely distributed bioactive flavonoid, has recently gained excellent attention among researchers as an effective anticancer drug that can alternate cancer-signaling pathways, induce programmed cell death, and reduce tumor growth in various cancer types. Despite its impressive anti-neoplastic activity, high hydrophobicity, and nonspecific biodistribution make apigenin difficult for pharmaceutical applications.

We highlighted the therapeutic potential of apigenin and its derivatives in different cancer types, along with their mechanism of action. Nanoengineered drug delivery systems have remarkable applications in minimizing drug degradation and enhancing the therapeutic efficacy of drugs with sustained release, prolonged blood retention time, and reduced off-target toxicities. This review has evaluated and explored the molecular interactions of this novel flavonoid in various cancer signaling pathways to selectively inhibit neoplastic development in multiple cancer types. To ensure the complete coverage of the explored research area, Google Scholar, PubMed, and Web of Science were used to find not only the most relevant but also connected and similar articles.

A comprehensive overview of apigenin nanotherapy in cancer treatment can establish a platform to overcome its difficulties for pharmaceutical applications and efficient clinical translation from bench to bedside.

Colorectal cancer (CRC) remains a significant global health challenge, demanding continuous advancements in treatment strategies. This review explores the complexities of targeting colorectal cancer stem cells (CSCs) and the mechanisms contributing to resistance to 5-fluorouracil (5-FU). The efficacy of 5-FU is enhanced by combination therapies such as FOLFOXIRI and targeted treatments like bevacizumab, cetuximab, and panitumumab, particularly in KRAS wild-type tumors, despite associated toxicity. Biomarkers like thymidylate synthase (TYMS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are crucial for predicting 5-FU efficacy and resistance. Targeting CRC-CSCs remains challenging due to their inherent resistance to conventional therapies, marker variability, and the protective influence of the tumor microenvironment which promotes stemness and survival. Personalized treatment strategies are increasingly essential to address CRC's genetic and phenotypic diversity. Advances in immunotherapy, including immune checkpoint inhibitors and cancer vaccines, along with nanomedicine-based therapies, offer promising targeted drug delivery systems that enhance specificity, reduce toxicity, and provide novel approaches for overcoming resistance mechanisms. Integrating these innovative strategies with traditional therapies may enhance the effectiveness of CRC therapy by addressing the underlying causes of 5-FU resistance in CSCs.

Multiple studies have raised concerns about the impact of long-term exposure to environmental pollutants on the occurrence and progression of cancer, but little is known about how these compounds affect the treatment of cancer patients. In this work, two common pollutants including benzo [a]pyrene (B [a]P) and catechol (CL) were tested for their chronic effects on the efficacy of common chemotherapeutic drug in lung cancer (A549) cells. Both pollutants were unlikely to be the substrates of ABC transporters, as their toxicity was unaffected by ABC transporter inhibitors. However, their repeated exposure led to the generation of chemoresistance to doxorubicin (DOX) and cisplatin (CDDP), indicating the formation of multidrug-resistance (MDR) cells. Compared with DOX-resistant cells, decreased expression of ABC transporters but increased responses were found in pollutants-resistant cells. In addition, pollutants-resistant cells were more potent in up-regulating anti-apoptosis, proliferation, and migration pathways, which were confirmed by the wound-healing and apoptosis assays. Overall, these results indicated a distinct MDR mechanism induced by non-substrate pollutants, and could be beneficial for understanding the environmental risk of pollutants in their "safe" concentrations.

I am an Associate Professor in the Department of Molecular Biosciences at Northwestern University. My research program investigates the structure, function, and regulation of membrane proteins, with a particular emphasis on ATP-binding cassette (ABC) importers. ABC transporters are a highly conserved superfamily of transmembrane proteins found across all organisms. These proteins utilize the energy from ATP binding and hydrolysis to transport of a broad array of substrates- including metabolites, lipids, peptides and drugs- across cellular membranes. In this perspective, I discuss how structural and biophysical characterization of ABC importers have significantly advanced our understanding of the mechanisms underlying their transport function. I also highlight the challenges in developing a unified mechanistic model and propose that the remarkable diversity of ABC transporters may necessitate multiple transport mechanisms for a complete picture of how these critical proteins function.

Growth hormone (GH) is a pituitary-derived endocrine hormone required for normal postnatal growth and development. Hypo- or hypersecretion of endocrine GH results in 2 pathologic conditions, namely GH deficiency (GHD) and acromegaly. Additionally, GH is also produced in nonpituitary and tumoral tissues, where it acts rather as a cellular growth factor with an autocrine/paracrine mode of action. An increasingly persuasive and large body of evidence over the last 70 years concurs that GH action is implicit in escalating several cancer-associated events, locally and systemically. This pleiotropy of GH's effects is puzzling, but the association with cancer risk automatically raises a concern for patients with acromegaly and for individuals treated with GH. By careful assessment of the available knowledge on the fundamental concepts of cancer, suggestions from epidemiological and clinical studies, and the evidence from specific reports, in this review we aimed to help clarify the distinction of endocrine vs autocrine/paracrine GH in promoting cancer and to reconcile the discrepancies between experimental and clinical data. Along this discourse, we critically weigh the targetability of GH action in cancer-first by detailing the molecular mechanisms which posit GH as a critical node in tumor circuitry; and second, by enumerating the currently available therapeutic options targeting GH action. On the basis of our discussion, we infer that a targeted intervention on GH action in the appropriate patient population can benefit a sizable subset of current cancer prognoses.

Drug resistance to chemotherapy in treating cancers becomes an increasingly serious challenge, which leads to treatment failure and poor patient survival. Drug-resistant cancer cells normally reduce intracellular accumulation of drugs by controlling drug uptake and promoting drug efflux, which severely limits the efficacy of chemotherapy. To overcome this problem, a membrane fused drug delivery system (MF-DDS) was constructed to treat cisplatin (DDP)-resistant lung cancer (A549-DDP) by delivering DDP via membrane fusion using a complementary coiled-coil forming peptides (CP8K4/CP8E4). The lipopeptide CP8K4 was pre-incubated firstly and decorated on the surface of A549-DDP cells, and then the cells interacted with the lipopeptide CP8E4 modified on the lipid bilayer (LB) coated PLGA nanoparticles loading DDP (PLGA-DDP@LB-CP8E4), leaded to the direct cytosolic DDP delivery and cancer cell death. Compared with free DDP, this MF-DDS achieved a 13.42-folds reduced IC50 value of A549-DDP cells in vitro, and tumor size was down-regulated, showing only 1/5.26 of the original weight in vivo. Meanwhile, the anti-drug resistant mechanism was explored, where the MF-DDS inhibited the expression of efflux protein genes, including MRP1, MRP2, and ABCG2, leading to increased intracellular drug accumulations. Altogether, this MF-DDS effectively delivered DDP into DDP-resistant cancer cells, making it a promising and improved pharmacological therapeutic approach for drug-resistant tumor treatment.

Multi-drug resistance-associated protein 1 (MRP1) plays critical roles in the multi-drug resistance (MDR) of cancer cells, LncRNA HOTAIR is closely related to MDR in lung cancer, however, the effects of HOTAIR on MRP1 expression and MDR in lung cancer cells (A549/DDP) remain unknown. In this study, the effects of HOTAIR on MRP1 gene expression and MDR in A549/DDP cells were monitored. LncRNA HOTAIR was upregulated in A549/DDP cells, and overexpression of HOTAIR promoted MRP1 expression and MDR development. The opposite trend was observed when HOTAIR was silenced in A549/DDP cells. To uncover the role of LncRNA HOTAIR in the MDR of human lung cancer, the effects of Egr1 on MRP1 gene expression and MDR in A549/DDP cells were monitored. The results showed that Egr1 could bind to the MRP1 promoter at site -53/-42 bp and regulate MRP1 expression. Egr1 knock-down reduced MRP1 expression, while Egr1 overexpression increased it. Further, the results demonstrated that LncRNA HOTAIR mediated the effects of Egr1 on MRP1 and MDR via sponging of miR-6807-3p. Moreover, miR-6807-3p exerts its function by targeting the Egr1 3'UTR. In conclusion, the results revealed the novel HOTAIR/miR-6807-3p/Egr1 axis in the regulation of MRP1 expression and MDR in lung cancer cells.

One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.

Overcoming multidrug resistance (MDR), which is often caused by the overexpression of ATP binding cassette (ABC) transporters in cancer cells remains a major challenge for cancer treatment. Receptor tyrosine kinase inhibitors have demonstrated potential in reversing MDR. This study aimed to investigate the effects of c-MET RTKIs on the reversal of MDR induced by ABCG2 in breast cancer cells.

MTT assay was employed to assess antiproliferative activity of c-MET inhibitors, including cabozantinib, crizotinib, and PHA665752. The accumulation of the fluorescent probe mitoxantrone was evaluated by flow cytometry. The drug-drug interaction in combination treatments was analyzed using CalcuSyn software.

The combination of cabozantinib, crizotinib, and PHA665752 with mitoxantrone resulted in synergistic effects in MDR cells. This was demonstrated by the mean CI values of 0.32 ± 0.07, 0.53 ± 0.05, and 0.59 ± 0.03, respectively. In the same cells, c-MET inhibitors enhanced the accumulation of mitoxantrone, with accumulation ratios ranging from 1.6 to 3.8, while no change was found in parental MCF-7 cells. Computational analysis revealed that the drug-binding region of ABCG2 transporters could be a viable target for these compounds.

c-MET inhibitors hold potential as effective agents for reversing MDR in ABCG2-medicated drug-resistant cancer cells.

Photoacoustic brain imaging (PABI) has emerged as a promising biomedical imaging modality, combining high contrast of optical imaging with deep tissue penetration of ultrasound imaging. This review explores the application of photoacoustic imaging in brain tumor imaging, highlighting the synergy between nanomaterials and state of the art optical techniques to achieve high-resolution imaging of deeper brain tissues. PABI leverages the photoacoustic effect, where absorbed light energy causes thermoelastic expansion, generating ultrasound waves that are detected and converted into images. This technique enables precise diagnosis, therapy monitoring, and enhanced clinical screening, specifically in the management of complex diseases such as breast cancer, lymphatic disorder, and neurological conditions. Despite integration of photoacoustic agents and ultrasound radiation, providing a comprehensive overview of current methodologies, major obstacles in brain tumor treatment, and future directions for improving diagnostic and therapeutic outcomes. The review underscores the significance of PABI as a robust research tool and medical method, with the potential to revolutionize brain disease diagnosis and treatment.

Methotrexate (MTX) is a critical antimetabolite drug in treating various pediatric diseases, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), brain tumors, osteosarcoma, inflammatory myofibroblastic tumor (IMT), juvenile scleroderma (JS), and juvenile idiopathic arthritis (JIA). MTX acts as a folate antagonist by inhibiting dihydrofolate reductase (DHFR), an enzyme essential for the synthesis of tetrahydrofolate. This disruption impairs DNA synthesis, repair, and cellular replication, particularly affecting rapidly dividing cells. Despite its efficacy, MTX resistance poses significant challenges, particularly in pediatric oncology, where it undermines the ability to achieve sustained therapeutic effects, resulting in reduced therapeutic efficacy and poor prognosis. The mechanisms of MTX resistance encompassed reduced enzyme activity pivotal for MTX metabolism, enhanced expression of efflux transporters, genetic variations, and alterations in signaling pathways. Multifaceted strategies have been explored to overcome MTX resistance. Combination therapies with ginger extract, gold nanoparticles, and arsenic trioxide (ATO) have been investigated to augment MTX's cytotoxic effects. Synergies with mTOR inhibitors and MDM2 inhibitors have demonstrated enhanced outcomes in ALL. In JIA, targeting ATP-binding cassette (ABC) transporters and modulating transforming growth factor‑β (TGF-β) signaling pathways have emerged as promising approaches. For osteosarcoma, emphasis on autophagy pathways and non-coding RNAs influencing chemotherapy sensitivity could enhance MTX effectiveness. This review delineates MTX's therapeutic roles, elucidates its resistance mechanisms, and discusses current and potential strategies for managing MTX resistance to bolster treatment effectiveness in pediatric tumors and other diseases. This knowledge base could underpin further research and development of personalized treatments to optimize MTX's clinical benefits.

Chemoresistance is one ofthe main challenges for advanced NPCtreatment.We previouslyproved LHX2 transcriptionally regulates FGF1 and promotes cancer progression through activating FGF1/FGFR axis,which prompted us toexplore the potential inhibitors for FGFR to improve the therapy response.

RT-qPCR, immunohistochemistry, western blot assayand immunofluorescencewere applied to verify the gene expression levels. Xenograftmodel as well as lung metastasis model was performed forin vitroassays. Flow cytometry and Tunel stainingwere used to determine the apoptosis of NPC cells.The interaction between β-eudesmol and FGFR1/2 was analyzed by Autodock software.

β-eudesmol inhibited the growth and metastasisof NPCin vivoandin vitro.In addition,β-eudesmol treatment promoted NPC apoptosis and sensitized NPC to cisplatin. β-eudesmol putatively bound to FGFR and blocked the Akt signaling, STAT3 signalingandERKsignaling,which in turn restrainedABCC1 transcription.

β-eudesmol suppressed cell growth, metastasis and chemoresistance in NPC through targetingFGF1/FGFR signaling, thereby blocking the Akt signaling, STAT3 signaling andERKsignaling, as well as down-regulating ABCC1 expression. Our findings provided a novel potential drug for NPC treatment.

Ion homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic inhibitor rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these compounds. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing compounds, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as an important modulator for microtubule-associated chemotherapy response.

Small-molecule compounds exhibit distinct pharmacological properties and clinical effectiveness. Over the past decade, advances in covalent drug discovery have led to successful small-molecule drugs, such as EGFR, BTK, and KRAS (G12C) inhibitors, for cancer therapy. Researchers are paying more attention to refining drug screening methods aiming for high throughput, fast speed, high specificity, and accuracy. Therefore, the discovery and development of small-molecule drugs has been facilitated by significantly reducing screening time and financial resources, and increasing promising lead compounds compared with traditional methods. This review aims to introduce classical and emerging methods for screening small-molecule compounds in targeted cancer therapy. It includes classification, principles, advantages, disadvantages, and successful applications, serving as valuable references for subsequent researchers.

Multidrug resistance mediated by P-glycoprotein (Pgp) is a significant obstacle to cancer chemotherapy. Taxane drugs, including paclitaxel, docetaxel, and cabazitaxel, are used to treat multiple types of cancer. All taxane drugs are Pgp substrates, but cabazitaxel is also a Pgp inhibitor, indicating potential differential interactions between Pgp and different taxanes. Here, we showed for the first time that cabazitaxel had a partial inhibitory effect on the ATPase activity at concentrations higher than 10 µM. We found the KD of paclitaxel, docetaxel, and cabazitaxel to Pgp are 0.85 µM, 40.59 µM, and 13.53 µM, respectively. Based on acrylamide quenching, paclitaxel induced Pgp into a wide inward-facing open conformation at a high concentration but a slightly occluded conformation at lower concentrations. Both docetaxel and cabazitaxel shifted Pgp towards occluded states, each drug resulting in a unique degree of occlusion. Furthermore, molecular docking and energy calculations revealed that cabazitaxel binds with the "access tunnel" and blocks the subsequent nucleotide-binding domain dimerization. Our results indicate that the preference of taxanes for different binding sites on Pgp leads to distinct transport mechanisms. These results provide valuable insight into the interaction between taxanes and Pgp, which will enhance future drug development.

Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with a significant impact on public health. Current treatment options include surgery, chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy. Despite advancements in these therapeutic modalities, resistance remains a significant challenge, often leading to treatment failure, poor progression-free survival, and cancer recurrence. Mechanisms of resistance in CRC are multifaceted, involving genetic mutations, epigenetic alterations, tumor heterogeneity, and the tumor microenvironment. Understanding these mechanisms at the molecular level is crucial for identifying novel therapeutic targets and developing strategies to overcome resistance. This review provides an overview of the diverse mechanisms driving drug resistance in sporadic CRC and discusses strategies currently under investigation to counteract this resistance. Several promising strategies are being explored, including targeting drug transport, key signaling pathways, DNA damage response, cell death pathways, epigenetic modifications, cancer stem cells, and the tumor microenvironment. The integration of emerging therapeutic approaches that target resistance mechanisms aims to enhance the efficacy of current CRC treatments and improve patient outcomes.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

The ATP-binding cassette (ABC) transporter family is among the largest protein superfamilies, consisting of seven subfamilies, and plays an important role in various physiological processes and in the clinical manifestations of many diseases. The early clinical signs of head and neck cancer (HNC) are often subtle, resulting in most patients being diagnosed at more advanced stages. This late diagnosis adversely affects tumor treatment, and the resistance of certain tumors to chemotherapy further poses significant challenges for clinical management. Several previous studies have indicated a correlation between the ABC protein family and multidrug resistance (MDR) in tumors. This article offers a thorough review of the subfamilies, structures, functions, and roles of ABC transporters in MDR related to head and neck tumors, with the aim of providing insights and recommendations for overcoming MDR in this context.

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting "undruggable" proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.

Multidrug ABC transporters harness the energy of ATP binding and hydrolysis to translocate substrates out of the cell and detoxify them. While this involves a well-accepted alternating access mechanism, molecular details of this interplay are still elusive. Rhodamine6G binding on a catalytic inactive mutant of the homodimeric multidrug ABC transporter BmrA triggers a cooperative binding of ATP on the two identical nucleotide-binding-sites, otherwise michaelian. Here, we investigate this asymmetric behavior via a structural-enzymology approach, solving cryoEM structures of BmrA at defined ATP ratios, highlighting the plasticity of BmrA as it undergoes the transition from inward to outward facing conformations. Analysis of continuous heterogeneity within cryoEM data and structural dynamics, reveals that Rhodamine6G narrows the conformational spectrum explored by the nucleotide-binding domains. We observe the same behavior for the other drug Hœchst33342. Following on these findings, the effect of drug-binding showed an ATPase stimulation and a maximal transport activity of the wild-type protein at the concentration-range where the cooperative transition occurs. Altogether, these findings provide a description of the influence of drug binding on the ATP-binding sites through a change in conformational dynamics.

Doxorubicin (DOX), an anthracycline, is widely used in cancer treatment by interfering RNA and DNA synthesis. Its broad antitumour spectrum makes it an effective therapy for a wide array of cancers. However, the prevailing drug-resistant cancer has proven to be a significant drawback to the success of the conventional chemotherapy regime and DOX has been identified as a major hurdle. Furthermore, the clinical application of DOX has been limited by rapid breakdown, increased toxicity, and decreased half-time life, highlighting an urgent need for more innovative delivery methods. Although advancements have been made, achieving a complete cure for cancer remains elusive. The development of nanoparticles offers a promising avenue for the precise delivery of DOX into the tumour microenvironment, aiming to increase the drug concentration at the target site while reducing side effects. Despite the good aspects of this technology, the classical nanoparticles struggle with issues such as premature drug leakage, low bioavailability, and insufficient penetration into tumours due to an inadequate enhanced permeability and retention (EPR) effect. Recent advancements have focused on creating stimuli-responsive nanoparticles and employing various chemosensitisers, including natural compounds and nucleic acids, fortifying the efficacy of DOX against resistant cancers. The efforts to refine nanoparticle targeting precision to improve DOX delivery are reviewed. This includes using receptor-mediated endocytosis systems to maximise the internalisation of drugs. The potential benefits and drawbacks of these novel techniques constitute significant areas of ongoing study, pointing to a promising path forward in addressing the challenges posed by drug-resistant cancers.

Targeted therapy represents a form of cancer treatment that specifically focuses on molecular markers regulating the growth, division, and dissemination of cancer cells. It serves as the cornerstone of precision medicine and is associated with fewer adverse effects compared to conventional chemotherapy, thus enhancing the quality of patient survival. These make targeted therapy as a vital component of contemporary anti-cancer strategies. Although targeted therapy has achieved excellent anti-cancer results, there are still many factors affecting its efficacy. Among the numerous factors affecting anti-cancer treatment, the role of intestinal bacteria and its metabolites are becoming increasingly prominent, particularly in immunotherapy. However, their effects on anticancer targeted therapy have not been systematically reviewed. Herein, we discuss the crosstalk between gut bacteria and anticancer targeted therapies, while also highlighting potential therapeutic strategies and future research directions.

Globally, prostate cancer (CaP) is a leading cause of death and disability among men and a substantial public health burden. Despite advancements in cancer treatment, chemoresistance remains a significant issue in cancer therapy, accounting for the majority of patient relapses and poor survival. Cancer stem cells (CSCs) are considered the main cause of cancer recurrence, chemoresistance, and poor survival of patients. These CSCs acquire stemness and chemoresistance by certain mechanisms such as enhanced DNA repair processes, increased expression of drug efflux pumps, resistance to apoptosis, and altered cell cycle and tumor microenvironment (TME).

We cover the latest developments in this field and give an overview of future research directions.

CSCs show dysregulation of several signaling pathways, mostly related to conferring chemoresistance phenotype, such as high drug efflux, apoptotic resistance, quiescent cell cycle, tumor microenvironment, and DNA repair. There are several research articles published on this topic. However, still, this field warrants further investigations to identify the therapeutic molecule that can either chemosensitize CSCs or kill them effectively. This can only be possible when we know the complete mechanisms to comprehend the fundamental causes of cancer stemness and therapy resistance.

Multidrug resistance-associated proteins (MRPs) have a widespread tissue distribution. They play an important role in drug disposition and drug-drug interactions (DDIs) and have been associated with various diseases. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to assess MRP1 function in the brain and lungs of mice. [11C]BMP crosses cellular membranes by passive diffusion followed by intracellular conjugation with glutathione and MRP1-mediated efflux of the radiolabelled glutathione-conjugate. In this study, we assessed the effect of the prototypical organic anion transporter inhibitor probenecid on the whole-body disposition of [11C]BMP to examine its suitability for measuring the function of MRP1 and possibly other MRP subtypes across multiple tissues.

Seven healthy volunteers (3 women, 4 men) underwent two dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP, without and with pre-treatment with a single oral dose of probenecid. Volumes of interest were outlined for several MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, skeletal muscle, kidneys, and liver). Tissue time-activity curves were corrected for the contribution of vascular radioactivity and the elimination rate constant (kE, h- 1) was calculated as a parameter for tissue MRP function.

Radioactivity was primarily excreted into the urinary bladder and urinary clearance was significantly decreased after probenecid administration (- 50 ± 16%). Following probenecid administration, kE was significantly decreased in the kidneys (- 43 ± 20%), liver (- 18 ± 15%), myocardium (- 16 ± 12%), skeletal muscle (- 51 ± 34%), and retina (- 57 ± 29%, non-blood-corrected).

Our study highlights the great potential of LAFOV PET/CT to assess drug disposition and transporter-mediated DDIs in humans at a whole-body, multi-tissue level. Due to the slow elimination of [11C]BMP-derived radioactivity from the human brain, [11C]BMP appears unsuitable to measure cerebral MRP1 function in humans, but it may be used to assess the function of MRP1 and possibly other MRP subtypes in various peripheral tissues.

EudraCT 2021-006348-29. Registered 15 December 2021.

Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.

The colon possesses a unique physiological environment among human organs, where there is a highly viscous body fluid layer called the mucus layer above colonic epithelial cells. Dysfunction of the mucus layer not only contributes to the occurrence of colorectal cancer (CRC) but also plays an important role in the development of chemoresistance in CRC. Although viscosity is an essential property of the mucus layer, it remains elusive how viscosity affects chemoresistance in colon cancer cells. In this study, the influence of viscosity on their chemoresistance was elucidated by culturing colon cancer cells in media of different viscosities supplemented with doxorubicin (DOX). The viscosity range was adjusted from 99.4 mPa s to 776.6 mPa s by adding polyethylene glycol of different molecular weights in culture medium. Cell viability in the high viscosity medium was higher than that in the low viscosity medium. Expression of chemoresistance-related genes such as ABCC2 and ABCG2 increased when cells were cultured in the high viscosity medium. Furthermore, cell migration increased while proliferation decreased when cells were cultured in the high viscosity medium. The colon cancer cells cultured in the high viscosity medium exhibited high expression of p21 mRNA. The results suggested that viscosity could affect the resistance of colon cancer cells to DOX by regulating the expression of chemoresistance-related and proliferation-related genes.

The study investigated microRNA-152-3p-mediated autophagy and sensitivity of paclitaxel-resistant ovarian cancer cells.

The miR-152-3p mimics and miR-152-3p inhibitor were transfected in A2780 cells and A2780T cells, and the scrambled sequences were transfected as a negative control group, the transfection efficiency was detected by qPCR technology. MTT was used to detect the proliferation and IC50 value of the cells after transfection. The expression of target proteins in A2780 cells and A2780T cells were detected by qPCR; The expression of phosphatase and tensin homolog (PTEN) and ATG4D after transfection were analyzed by Western blot. The knockdown efficiency of PTEN was detected by reverse qRT-PCR, MTT and Western blot.

The expression level of miR-152-3p in A2780T cells was 52-fold higher than that in A2780 cells according to the results of qPCR. Downregulation of miR-152-3p reversed PTX-induced autophagy, inhibited cell proliferation and apoptosis, and reduced drug resistance in A2780T cells. Moreover, PTEN appeared to be a potential target of miR-152-3p, and low expression levels of miR-152-3p increased PTX sensitivity by downregulating PTEN in vitro.

PTEN may be a novel therapeutic target gene for patients with PTX-resistant ovarian cancer. These findings provide a potential translational framework for developing novel therapeutic strategies to overcome paclitaxel resistance in ovarian cancer.

We report the occurrence of acquired tumor cell resistance to 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) in combination with ABCG2 inhibition. ALA-PDT in combination with either an ABCG2 tool inhibitor Ko143 or a repurposed clinically-relevant ABCG2 inhibitor lapatinib was highly effective in eradicating the H4 human glioma cells, resulting in minimal cell survival after treatment. However, after seven rounds of repeated treatments with light dose escalation, the resultant tumor cells became resistant to the combination therapy. The resistant sublines and the parental cell line showed similar ABCG2 activities and protein levels, indicating that it was not ABCG2 that caused the resistance. They also exhibited similar responses to PpIX-PDT and mTOR inhibitor AZD2014, suggesting that alterations in PDT sensitivity and mTOR pathway had little contribution to the development of resistance phenotype. By determining the intracellular and extracellular PpIX levels, the activities and protein levels of heme biosynthesis enzymes, we found that porphobilinogen deaminase (PBGD) activity and protein level were significantly reduced in the resistant sublines, causing resistance to PDT by substantially reducing PpIX biosynthesis. A novel acquired resistance mechanism to ALA-PDT with ABCG2 inhibition has been uncovered.

Poor response to 5-fluorouracil (5-FU) remains an obstacle in the treatment of gastric cancer (GC). Super enhancers (SEs) are crucial for determining tumor cell survival under drug pressure. SE landscapes related to 5-FU-resistance are mapped to GC using chromatin immunoprecipitation-sequencing (ChIP-Seq). SiRNA transcription factors (TFs) screen determines master TF Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) activated by SE. High NR3C1 expression driven by SE correlated with 5-FU resistance in patient-derived organoids (PDOs). Phase separation formed by NR3C1 is observed using fluorescence recovery after photobleaching (FRAP). NR3C1 protein and Mediator promoted SE-related gene transcription via phase separation. SEs and NR3C1 co-binding patterns are explored using Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing. 5-FU-related genes driven by NR3C1 are identified using epigenetic reader inhibitor JQ1 and NR3C1 specific inhibitor Cort108297. NR3C1 knockdown increases 5-FU sensitivity and alters the SE landscape through enhancer reprogramming, reducing downstream 5-FU-related target genes. JQ1 and Cort108297 both improve 5-FU efficacy in PDOs and patient-derived xenografts (PDXs) by destroying SEs or inhibiting NR3C1. In conclusion, SE-driven NR3C1 promotes 5-FU resistance in GC. SE destruction and NR3C1 inhibition lead to enhancer reconstruction and reduce 5-FU-related gene transcription, providing alternative therapeutic strategies for improving 5-FU sensitivity.

ATP-binding cassette (ABC) transporters are proteins responsible for active transport of various compounds, from small ions to macromolecules, across membranes. Proteins from this superfamily also pump drugs out of the cell resulting in multidrug resistance. Based on the cellular functions of ABC-transporters they are commonly associated with diseases like cancer and cystic fibrosis. To understand the molecular mechanism of this critical family of integral membrane proteins, structural characterization is a powerful tool which in turn requires successful recombinant production of stable and functional protein in good yields. In this review we have used high resolution structures of ABC transporters as a measure of successful protein production and summarized strategies for prokaryotic and eukaryotic proteins, respectively. In general, Escherichia coli is the most frequently used host for production of prokaryotic ABC transporters while human embryonic kidney 293 (HEK293) cells are the preferred host system for eukaryotic proteins. Independent of origin, at least two-steps of purification were required after solubilization in the most used detergent DDM. The purification tag was frequently cleaved off before structural characterization using cryogenic electron microscopy, or crystallization and X-ray analysis for prokaryotic proteins.

Biological nanotechnologies based on functional nanoplatforms have synergistically catalyzed the emergence of cancer therapies. As a subtype of metal-organic frameworks (MOFs), zeolitic imidazolate frameworks (ZIFs) have exploded in popularity in the field of biomaterials as excellent protective materials with the advantages of conformational flexibility, thermal and chemical stability, and functional controllability. With these superior properties, the applications of ZIF-based materials in combination with various therapies for cancer treatment have grown rapidly in recent years, showing remarkable achievements and great potential. This review elucidates the recent advancements in the use of ZIFs as drug delivery agents for cancer therapy. The structures, synthesis methods, properties, and various modifiers of ZIFs used in oncotherapy are presented. Recent advances in the application of ZIF-based nanoparticles as single or combination tumor treatments are reviewed. Furthermore, the future prospects, potential limitations, and challenges of the application of ZIF-based nanomaterials in cancer treatment are discussed. We except to fully explore the potential of ZIF-based materials to present a clear outline for their application as an effective cancer treatment to help them achieve early clinical application.