Although cisplatin (CDDP) is widely employed in combination immunotherapy, no CDDP-based regimen has shown a survival benefit when treating the ovarian cancers. This is mainly because the impact of CDDP on immunotherapy is not fully understood. A critical gap concerns how CDDP reshape the tumour microenvironment, especially through extracellular vesicles (EVs)-mediated communication. In this work, using human and murine ovarian cancer cells as a model, we demonstrate that CDDP boosts the secretion of EVs from cancer cells, while exerting no such effect on non-cancerous cells. These CDDP-induced tumour-derived EVs, in turn, drive the differentiation of CD4+ T cells towards immunosuppressive regulatory T cells (Treg cells), which are known to limit the efficacy of immunotherapy. Based on next-generation sequencing, a significant enrichment of miR-181a-5p was identified in CDDP-induced tumour-derived EVs, and further functional studies confirmed that this microRNA promoted Treg cell differentiation via suppressing sirtuin 1 (SIRT1), a key regulator of the transcription factor forkhead box protein P3 (FOXP3). Importantly, inhibition of miR-181a-5p abrogated the Treg-promoting effect of CDDP-induced tumour-derived EVs, a finding further validated in vivo, where blockade of miR-181a-5p not only impaired Treg differentiation but also restored T-cell-mediated antitumour immunity and restrained tumour growth. Together, these findings uncover a previously unrecognised mechanism by which CDDP exacerbates immunosuppression via miR-181a-5p-enriched EVs and suggest that targeting this pathway could improve the therapeutic efficacy of combination immunotherapy in ovarian cancer.

To elucidate how ALX Homeobox 4 (ALX4) modulates cisplatin sensitivity via DNA damage regulation in breast cancer (BC), this study explored the established role of mRNA-mediated DNA repair in driving chemoresistance.

This study designs and synthesizes a series of vitexin derivatives to evaluate their inhibitory activity against human colon cancer HCT-116 cells and to explore the underlying mechanisms. Antiproliferative effects are assessed using the CCK-8 assay. Molecular docking with Schrödinger software and molecular dynamics simulations analyze interactions between candidate compounds and CDK1. Cell cycle distribution is determined by flow cytometry, while western blotting, immunofluorescence, and CDK inhibition assays evaluate CDK1/cyclin B expression. Most derivatives show stronger inhibitory activity than the parent compound. Vitexin exhibits an IC₅₀ of 210.23 ± 40.89 μM, whereas Butylated vitexin (M3) displays markedly enhanced potency (IC₅₀ = 8.73 ± 1.40 μM) and induces G₂/M phase arrest. Molecular docking reveals strong binding affinity between M3 and CDK1 (Docking score -10.127), and molecular dynamics simulations confirm the stability of the M3-CDK1 complex with inhibitory effects comparable to flavopiridol (FP). Furthermore, M3 downregulates CDK1/cyclin B expression in HCT-116 cells (IC₅₀ = 9.83 ± 2.65 μM). M3 may suppress HCT-116 cell proliferation by targeting CDK1/cyclin B and inducing G₂/M phase arrest.

This network meta-analysis evaluated the efficacy of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, with or without Dexamethasone (D), for preventing chemotherapy-induced nausea and vomiting (CINV) in patients undergoing highly emetogenic chemotherapy (HEC) who were limited to these regimens.

Cancer stem cells (CSCs) contribute to an immunosuppressive microenvironment through complex mechanisms and tumor-immune interactions. However, the key determinants of CSC characteristics in driving tumor progression, immune suppression, and response to ICIs remain unclear and require systematic investigation. This study developed a quantitative systems pharmacology (QSP) model covering various CSC properties, thereby capturing the temporal dynamics and CSC-immune interactions in triple-negative breast cancer (TNBC). Using the unified longitudinal dataset of tumor growth, CSC frequency, and immune cell dynamics that we obtained from BALB/c mice bearing wild-type or Cd274-knockout 4T1 cells under various inoculation conditions, which provides multi-dimensional insights into CSC-related biology, the QSP model was calibrated and validated. Simulations and sensitivity analysis indicated that TNBC tumors with strong stemness exhibited significantly accelerated tumor growth and reduced infiltration of cytotoxic immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. These were associated with CSCs' enhanced self-renewal capacity, stemness maintenance, secretion of transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF), and PD-1/PD-L1-mediated immunosuppression. ICIs showed minimal efficacy in tumors with enhanced stemness, which was also linked to the aforementioned characteristics. Both the administration sequence and initiation timing of ICIs differentially influenced the therapeutic outcomes. These findings elucidate the roles of CSCs in TNBC progression, tumor immunity, and ICI efficacy while identifying the key underlying CSC characteristics, suggesting the potential value of assessing CSC biomarkers or abundance before ICI treatment and support the development of ICIs and anti-CSC combination therapies.

This study aimed to investigate institutional factors associated with the clinical implementation of gonadotropin-releasing hormone (GnRH) analogs for ovarian protection in women receiving chemotherapy among fertility preservation facilities in Japan.

Multiple myeloma (MM) is an incurable hematological malignancy with excessive bone marrow infiltration and pro-inflammatory microenvironment. In clinical practice, melphalan, an alkylating agent, and dexamethasone, a glucocorticoid widely used in MM regimens, provide clinical benefits. However, their efficacy is still limited by systemic toxicity, poor tumor selectivity, and the difficulty maintaining a predefined drug ratio at the tumor site. To address these challenges, we designed a supramolecular peptide-drug conjugate prodrug nanosystem (HMD NPs) composed of β-cyclodextrin-modified hyaluronic acid (HA-β-CD) scaffold and dual-drug conjugates, Ada-M-GFLG-D. In this design, MA and DEX are conjugated via a cathepsin B-cleavable GFLG linker and functionalized with adamantane for host-guest assembly, which allows co-delivery of the two drugs at a fixed 1:1 stoichiometric ratio. The resulting HMD NPs exhibited excellent stability, efficient cellular uptake. Ada-M-GFLG-D remains encapsulated within nanoparticles under physiological conditions. However, upon exposure to MM-mimicking intracellular conditions, HMD NPs undergo an enzyme-activation process, rapidly releasing both drugs. Cellular experiments demonstrate potent anti-tumor effects and significant downregulation of inflammatory pathways. In animal models, HMD NPs markedly suppress tumor progression, reducing bone marrow infiltration, relieving osteolytic damage, and showing favorable biocompatibility. These findings provide a promising strategy for improving therapeutic efficacy against MM.

An exopolysaccharide (EPS) isolated from Enterococcus faecium was functionalized with folic acid (FA) via carbodiimide-mediated coupling using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-Hydroxysuccinimide. This reaction facilitated the formation of an amide linkage between the primary amine group of FA and the carboxyl group of the EPS. The synthesized FA-functionalized EPS (FA-EPS) was further incorporated into a photothermally active coordination polymer matrix along with an anticancer drug to achieve a controlled drug release system targeting SH-SY5Y neuroblastoma cells. Physical interactions between polar groups of FA-EPS and drugs, including hydrogen bonding, electrostatic forces, and π-π stacking, enable efficient drug encapsulation within the FA-EPS matrix, resulting in controlled and sustained drug release that enhances therapeutic efficacy and minimizes toxicity. Moreover, the integration with the coordination polymer imparted photothermal properties, resulting in a synergistic enhancement of apoptosis through combined chemo-photothermal therapy. Flow cytometric analysis was subsequently performed to evaluate apoptosis in SH-SY5Y cells treated with the prepared composites, confirming the targeted and multifunctional therapeutic efficacy of these composites.

Pancreatic ductal adenocarcinoma (PDAC) is the most malignant tumor with dismal prognosis. The chemotherapy effect of PDAC is limited and has severe side effects. Hence, identifying a natural leading compound with high efficacy against PDAC is urgently needed. Chrysanthemum morifolium (C. morifolium), a traditional Chinese medicinal herb with reported antitumor properties, was hypothesized to contain polysaccharides with therapeutic efficacy against PDAC. A novel homogeneous RG-I pectin, HJ222, was successfully isolated and purified. Structural analysis shows that HJ222 possesses a backbone composed of repeating →2-α-Rhap-(1 → 4)-α-GalpA-(1 → units, with side chains extending from the O-4 position of 2,4-α-Rhap and certain 3,4-α-GalpA residues, forming galactose- and arabinose-rich branches. In vitro and in vivo assays demonstrate that the sulfated derivative S3HJ222 of HJ222 can significantly suppress pancreatic cancer cell proliferation and completely retard tumor growth in patient-derived xenograft mouse models. Mechanistic studies reveal that S3HJ222 can induce ferroptosis-a non-apoptotic form of cell death-by elevating intracellular Fe2+ and reactive oxygen species (ROS). Furthermore, S3HJ222 directly binds and stabilizes transferrin receptor (TFRC), and activates the acyl-CoA synthetase long-chain family member 4 (ACSL4) signaling axis. Collectively, S3HJ222 may be a promising active compound for the development of new anti-PDAC drugs.

Tumor heterogeneity, immunosuppression, and frequent adverse effects present major challenges in colorectal cancer therapy. Although the combination of oxaliplatin (OXA, chemotherapy) and fruquintinib (FRU, antiangiogenic) shows clinical promise, their divergent physicochemical properties and inadequate tumor selectivity lead to suboptimal efficacy and systemic toxicity. To overcome the challenge, we developed a tumor-targeted nanosystem based on chitosan and fucoidan for co-delivery of hydrophilic oxaliplatin and hydrophobic fruquintinib (CS-Arg/Fuc-Bio@OF). The nanoparticle leverages the inherent P-selectin affinity of fucoidan and active targeting given by biotin modification to achieve precise tumor accumulation and microenvironment-responsive drug release. In vitro studies demonstrated that CS-Arg/Fuc-Bio@OF effectively eliminated HCT116 and HT29 cancer cells by inducing robust immunogenic cell death (ICD) and exerted potent anti-angiogenic effects. The combination of OXA-induced ICD with FRU-mediated angiogenesis suppression and polysaccharide-promoted immunomodulation synergistically reprogrammed the immunosuppressive tumor microenvironment, facilitating an effective anti-tumor immune response. In vivo, the nanoparticles significantly inhibited tumor growth and demonstrated good biosafety, with a hemolysis rate < 5% and no appreciable organ toxicity observed. This work not only validates CS-Arg/Fuc-Bio@OF as an efficient and safe combination therapy carrier but also provides a novel strategy for developing drug delivery systems based on natural polysaccharides.

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, exhibits a 5-year survival rate below 10% and extremely poor clinical prognosis. Over 90% of PDAC patients harbor KRAS gene driver mutations, which promote tumor proliferation, invasion, and immunosuppression of the tumor microenvironment through constitutive activation of downstream RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Although the therapeutic potential of targeting KRAS has been recognized for decades, its smooth protein structure and lack of traditional drug-binding pockets led to its long-standing classification as an "undruggable" target, resulting in limited efficacy of early targeted agents. Recent breakthroughs with next-generation KRAS inhibitors have transformed the therapeutic landscape for pancreatic cancer. This review synthesizes evidence from basic research and clinical translation to provide a theoretical foundation and practical guidance for the precision treatment of KRAS-mutant pancreatic cancer.

Patient-derived cells (PDCs) and patient-derived organoids (PDOs) are complementary preclinical models widely used in translational cancer research. However, their molecular and functional differences have not been systematically characterized. This study established and analyzed paired PDC and PDO models derived from the same gastric cancer ascites to delineate platform-dependent molecular and functional profiles.

Narcolepsy is a rare disorder of central hypersomnolence which is often under-recognised owing to a variable clinical phenotype. Narcolepsy type 1 (NT1) is caused by loss of hypothalamic hypocretin (orexin) secreting neurons, which function to maintain wakefulness. There is strong evidence that NT1 is an immune-mediated disorder associated with the class II human leucocyte antigen DQB1*06:02 allele. Immune checkpoint inhibitors have revolutionised the treatment of many cancers; however, through their mechanism of action, they are associated with immune-related adverse effects. We describe a complex case of NT1 following ipilimumab and nivolumab exposure for management of metastatic melanoma.

Hypoxia-inducible factors 1 and 2 (HIF-1/2) function as master regulators of cancer progression by regulating angiogenesis, cancer stem cell specification, epithelial-mesenchymal transition, immune evasion, tissue invasion, and metastasis. We utilized computer-aided drug discovery and cell-based reporter assays to identify dual HIF-1/2 inhibitors, which bind directly to highly conserved domains of HIF-1α and HIF-2α, disrupt dimerization with HIF-1β, and trigger proteasomal degradation, thereby inhibiting HIF-1/2 transcriptional activity. These inhibitors and derivative compounds block growth and vascularization of breast, colorectal, head/neck, melanoma, and prostate tumors as monotherapy, and overcome resistance to anti-CTLA-4 or anti-PD-1 immunotherapy, with an aggregate complete response rate of over 50%, through reprogramming of the tumor immune cell microenvironment. Compared with the HIF-2-selective inhibitors belzutifan and PT2385, dual HIF-1/2 inhibitor 1.21S9N showed superior activity against breast and colorectal cancer models, respectively. PT2385 caused breathing abnormalities, whereas 1.21S9N did not. The drugs are orally bioavailable, and no safety concerns were identified even after extended or supratherapeutic dosing.

The longitudinal patterns of patient-reported outcomes and their association with mortality in routine oncology care are largely unexplored.

Hypoalbuminemia is a common clinical biomarker associated with poor outcomes in cancer patients. While it correlates with resistance to immune checkpoint inhibitors (ICIs), the direct functional role and underlying mechanisms in driving immunotherapy resistance remain unclear. In our study, we demonstrated that hypoalbuminemia directly drives ICIs resistance by orchestrating an immunosuppressive tumor microenvironment (TME) through impaired macrophage arginine metabolism. In a C57/BL model, low-protein diet-induced hypoalbuminemia mice bearing LLC tumors showed poor response to immunotherapy. Comprehensive immune profiling revealed a suppressed TME, characterized by reduced CD8+ T cell infiltration and increased macrophage abundance. Depletion of tumor-associated macrophages (TAMs) alleviated this immunosuppression. Transcriptomic analysis of TAMs from low-protein diet-induced hypoalbuminemia mice revealed a significant downregulation of the arginine biosynthesis pathway, which was consistent with observed reductions in systemic arginine levels. Crucially, dietary arginine supplementation successfully reversed the immunosuppressive phenotype and restored ICIs efficacy. However, this restorative effect of arginine is significantly dependent on its action on macrophages. Our findings establish low-protein diet-induced hypoalbuminemia as a key driver of immunotherapy resistance, unveil a novel metabolic-immune circuit centered on TAM arginine metabolism, and identify arginine replenishment as a potential therapeutic strategy to reverse immune suppression in hypoalbuminemia patients.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The epigenetic regulator EZH2 is a promising therapeutic target due to its role in tumor progression and therapy resistance. This study combined computational and experimental methods to repurpose FDA-approved drugs as EZH2 inhibitors. Virtual screening and molecular dynamics simulations identified acetyldigitoxin (ADT) as a potent EZH2 inhibitor, demonstrating superior binding affinity (-10.90 kcal/mol) and complex stability compared to the known inhibitor GSK126. ADT formed robust hydrogen bonds and hydrophobic interactions with key residues in the EZH2 binding site, supported by favorable binding free energy calculations (ΔGbinding = -34.73 kcal/mol). In vitro, ADT exhibited selective cytotoxicity against NSCLC A549 cells (IC₅₀ = 32.4 nM) versus normal bronchial epithelial cells (IC₅₀ = 190 nM). Treatment with ADT significantly reduced EZH2 expression and potently inhibited its histone methyltransferase activity, as directly evidenced by decreased global H3K27me3 levels. ADT induced G0/G1 cell cycle arrest and promoted apoptosis, accompanied by upregulation of pro-apoptotic genes (Bax, Caspase-3) and downregulation of anti-apoptotic (Bcl-2) and cell cycle (CyclinD1) genes. Our integrated findings position ADT as a repurposed drug candidate for targeting EZH2 in NSCLC, warranting further preclinical investigation including direct enzyme inhibition assays.

Cyclin-dependent kinase 16 (CDK16), a serine/threonine protein kinase, is a critical regulator of cell cycle progression, vesicle trafficking, and apoptosis. Its dysregulation is implicated in the progression of aggressive cancers, including triple-negative breast, lung, and prostate cancer, where its overexpression correlates with poor prognosis. Despite its therapeutic promise, CDK16 remains an understudied kinase lacking selective inhibitors, underscoring the need for innovative discovery approaches. This study introduces a novel computational framework that leverages multiple docked poses to augment datasets for regression-based machine learning (ML) models targeting CDK16 inhibition. This data augmentation strategy incorporated docking scores, ligand-receptor contact fingerprints (LRCFs), and conformation-sensitive physicochemical descriptors as input features. To our knowledge, this is the first application of docked pose augmentation for a regression-based drug discovery model. A systematic evaluation of eight ML algorithms across multiple docking score consensus levels identified Gradient Boosted Trees as the optimal learner. The Genetic Function Algorithm was integrated to select a minimal set of descriptors, which improved model generalizability. The resulting validated ML-QSAR model guided the generation of a robust pharmacophore model, which was used for virtual screening of the NCI and OpnMe databases. Subsequent in vitro LanthaScreen kinase assays confirmed two novel and potent CDK16 inhibitors: compound H_28 (OpnMe code: BI-831266) with an IC50 of 3.5 µM, and H_33 (OpnMe code: BI-1282) with an IC50 of 5.8 µM. These findings highlight the efficacy of integrating docked pose augmentation with regression modeling and experimental validation, offering a robust framework for accelerating the discovery of targeted anticancer agents.

Interleukin-18 (IL-18) is a pro-inflammatory cytokine, and higher IL-18 expression in pancreatic tumors is associated with poor prognosis. Although 5-fluorouracil (5-FU) has been reported to induce the release of bioactive (mature/cleaved) IL-18 from the pancreatic cancer cell line Capan-2, the underlying mechanism remains unclear. Here, we investigated IL-18 activation in pancreatic cancer cells after 5-FU treatment under low-nutrient conditions that mimic key features of the tumor microenvironment, using a monoclonal antibody we generated that specifically recognizes cleaved, active IL-18. We detected the release of active IL-18 from both Capan-2 and MIA PaCa-2 cells after 5-FU treatment. Analysis of separated attached and detached cell fractions showed that IL-18 cleavage occurred predominantly in detached cells. We also clarified that caspase-8-but not caspase-1/4-was activated in detached cells and was required for IL-18 and GSDMD cleavage that is a hallmark of pyroptosis. Surprisingly, detached cells from only nutrient starvation showed the same phenomenon, and 5-FU contributed to increased pyroptotic cells. On the other hand, the release of active IL-18 was not observed with gemcitabine. These findings suggest that a low-nutrient tumor microenvironment and 5-FU therapy can promote caspase-8-dependent pyroptotic cell death with IL-18 activation, potentially contributing to chronic inflammation in pancreatic tumors.

Immune checkpoint inhibitors (ICPis) are associated with islet function impairment (IFI), manifesting as hyperglycemia, diabetes mellitus (DM), or diabetic ketoacidosis (DKA). Delayed detection and management may lead to irreversible β-cell damage and life-threatening complications. We conducted a systematic review and meta-analysis to assess the risk of IFI associated with ICPis.