Blocking the p53-MDM2 and/or p53-MDMX protein-protein interaction (PPI) by small-molecule inhibitors has been tracked as a potentially effective cancer treatment approach. Herein, we present the discovery of a new series of spirooxindole-tethered pyrazolopyridine derivatives. The development of the new congeners was based on the analysis of the co-crystal structures of the inhibitors bound to both MDM2 and MDMX and studying the binding interactions between the substituents of small molecules and the three subpockets of the p53-MDM2/MDMX. The spirooxindoles 6b, 6k, and 6n attained the most pronounced activity in the MULTI-ARRAY MDM2-p53 complex assay with IC50 values of 1.26, 1.30, and 1.25 µM, respectively, in comparison with nutlin-3 (IC50 = 2.03 µM). The counterparts 6b, 6k, and 6n also revealed notable inhibitory potential against p53-MDMX. The antiproliferative efficacy of the most active target compounds was assessed in HCT-116 colon cancer cell line that overexpressed MDM2 and harbored wild-type p53. The derivative 6k accomplished the highest antiproliferative activity against HCT-116 compared to nutlin-3. Moreover, 6k displayed minimal toxicity compared to the reference nutlin-3 when examined on a normal cell line. Flow cytometric analysis revealed that 6k controlled cell growth via cell cycle arrest at the G1 phase and induced cell death via apoptosis. Additionally, compound 6k revealed a prominent effect in raising p53 levels with a 6.464-fold increase compared to the control. Molecular docking and molecular dynamics simulations justified the observed efficacy. Collectively, this study showcased a new class of potent p53-MDM2/MDMX dual inhibitors possessing a spirooxindole scaffold which can be subjected to future development.

Distal cholangiocarcinoma (dCCA) is a malignant tumor characterized by a challenging diagnosis, high invasiveness, and extremely poor prognosis. Research on dCCA is limited by the scarcity of reliable patient-derived preclinical tumor models. This study established a novel human distal cholangiocarcinoma cell line, CBC3T-3, and systematically characterized its biological properties, genomic features, and potential for clinical application. This cell line was extracted from postoperative distal cholangiocarcinoma tumor from a 54-year-old male patient. It was stably passaged (> 50 generations) through primary culture and condition optimization, preserving the same pathology as that of the primary tumor. Whole-exome sequencing (WES) confirmed somatic mutations, tumor mutation burden, single-sample clonal structure, driver genes, and drug resistance genes in CBC3T-3 cells, revealing their genomic characteristics. Functional assays demonstrated that CBC3T-3 cells exhibit strong capabilities for proliferation, migration, and invasion in vitro. In a subcutaneous xenograft model in immunodeficient mice, palpable tumor nodules developed within 4 weeks, reflecting the clinical characteristics of rapidly progressive disease. Drug sensitivity analysis revealed that, compared with TFK-1 cells, CBC3T-3 cells presented significantly greater responses to paclitaxel, gemcitabine, and oxaliplatin but relatively poor responses to 5-FU and cisplatin. The integration of drug resistance gene findings from WES suggests that TP53 missense mutations may mediate primary resistance to cisplatin. The establishment of the CBC3T-3 cell line enhances the research toolkit for dCCA. Its genomic characteristics and functional plasticity provide a reliable preclinical tumor model for developing precision therapies and investigating drug resistance mechanisms.

Resistance to 5-fluorouracil (5-FU) remains a major challenge in the treatment of colorectal cancer (CRC). Here, we identify ETS variant transcription factor 7 (ETV7) as significantly upregulated in CRC tissues and cell lines, with elevated expression associated with poor clinical prognosis. Functional assays demonstrate that ETV7 enhances CRC cell proliferation, invasion, and resistance to 5-FU. Mechanistically, ETV7 transcriptionally upregulates CXCL1, leading to increased neutrophil recruitment and enhanced formation of neutrophil extracellular traps (NETs). The resulting NETs-enriched tumor microenvironment promotes tumor aggressiveness and chemoresistance. Pharmacological inhibition of CXCL1 or degradation of NETs effectively attenuates ETV7-driven malignant phenotypes in vitro and in vivo. Collectively, these findings establish an ETV7-CXCL1-NETs axis that contributes to 5-FU resistance in CRC and suggest that targeting this pathway may improve chemotherapy response.

Although targeted therapy has made significant advances in cancer treatment throughout these years, drug resistance still remains a major obstacle. Plenty of evidence has proved that abnormal expression of receptor tyrosine kinase AXL is associated with targeted therapy resistance and poor clinical outcomes. AXL drives drug resistance through diverse mechanisms, including altering tumor cell phenotypes, orchestrating DNA damage response process, promoting the activation of bypass signals, or interacting with other receptor tyrosine kinases. Preclinical and clinical studies have demonstrated that combined inhibition of AXL and the other target can enhance the efficacy of various targeted therapies and improve outcomes for patients with drug resistance. This review summarizes recent advances in the specific roles of AXL in targeted therapy resistance and AXL-targeted treatment strategies. It further explores the potential clinical value of combinatorial approaches involving AXL inhibition and discusses future directions for its application in developing novel targeted therapies and advancing precision oncology treatment. 
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Tumor mutational burden (TMB) and PD-L1 are established biomarkers for guiding immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC). As ICI use expands into early-stage disease, we explored the feasibility of using TMB, which can be determined via a comprehensive genomic profiling assay along with EGFR and ALK genomic alterations, as a biomarker for outcomes in both neoadjuvant and adjuvant settings. TMB-high status (≥10 mut/Mb) showed a numerically higher, but not statistically significant, rate of pathological complete response among patients receiving neoadjuvant ICI and significantly associated with more favorable time to recurrence in patients receiving adjuvant ICI, particularly among patients with PD-L1 expression <50%. TMB should be considered in future early-stage NSCLC ICI clinical trials to further validate these results.

Prostate cancer (PCa) is the second most common cancer in men and shows high inter- and intra-patient heterogeneity. Consequently, treatment options are limited and there is a lack of representative preclinical models. Here, we establish a comprehensive biobank of murine organoids and tumoroids that reflect common patient mutations. We demonstrate that the deletion of Pten alone, or in combination with Stat3, or Tp53, drives the activation of cancer-related pathways in both prostate organoids and tumor-derived tumoroids. A medium-throughput drug screen identified two potent compounds, the PDPK1/AKT/FLT dual pathway inhibitor and the sirtuin inhibitor tenovin-6, which effectively suppressed tumoroid proliferation. Notably, these compounds also inhibited the growth of several human PCa cell lines and displayed synergistic effects when combined with the standard-of-care antiandrogen enzalutamide. Together, our findings provide evidence that murine tumoroids are versatile preclinical models for studying PCa tumorigenesis and drug sensitivities to develop therapeutic options for PCa patients.

Chronic inflammation is being recognised as a pivotal contributor to the onset and progression of cancer and other severe conditions. The cyclooxygenase (COX) is an essential enzyme in inflammation. Although this enzyme is typically overexpressed by inflammation, in many diseases like liver cirrhosis, thyroiditis, multiple sclerosis, neurological disorders, rheumatoid arthritis, Crohn's disease, ulcerative colitis, and cancer, its level increases persistently. This consistent expression contributes to its crucial role in tumour initiation and development. Additionally, COX-2 plays a dual role, generating both pro- and anti-inflammatory mediators, highlighting its multifaceted, dichotomous nature. Because of its dual role and significant implication in several diseases, it is now seen as a vital target in medicinal chemistry, leading to the development of drugs that specifically block its activity. In this work, we focus on the strong correlation between long-term inflammation and cancer. Furthermore, it explains the key molecular processes involved in this link. It also provides an overview of recent progress in clinical trials, along with FDA-approved drugs, showing their role and importance in treating such conditions. Recent developments over the last seven years (2020-2026) have been analysed, with a particular focus on scaffolds bearing five-membered azole-based heterocyclic compounds. It also provides an insightful resource for medicinal chemists working on the rational design and development of new molecules for the management of inflammation and cancer. Furthermore, oncologists and pharmacologists need to understand the evolving therapeutic model for COX-2-targeted drugs.

Cervical cancer remains a major global health burden. Although PD-1/PD-L1 immune checkpoint blockade has expanded treatment options, durable responses are still limited. One key reason is that tumor cells sustain immunosuppression by maintaining high levels of mature, N-glycosylated PD-L1 on the plasma membrane. This limitation highlights the need for approaches that disrupt PD-L1 maturation and stability rather than merely blocking ligand-receptor binding. UM-6, a melittin-derived fusion peptide, addresses this need by retaining antitumor activity while exhibiting markedly lower hemolysis than native melittin. In tumor models, UM-6 slowed tumor progression, reduced proliferation, and increased apoptosis. In parallel, it reshaped the tumor immune microenvironment by enhancing cytotoxic T-cell activity and mitigating PD-1-associated T-cell exhaustion. Mechanistically, UM-6 impaired PD-L1 N-glycosylation and reduced PD-L1 association with STT3A, which led to endoplasmic-reticulum retention, increased polyubiquitination, and accelerated ERAD/proteasome-mediated degradation, ultimately reducing functional PD-L1 at the cell surface. Together, these results support UM-6 as a peptide-based, mechanistically distinct strategy that targets PD-L1 biogenesis to relieve immunosuppression in cervical cancer.

To check the hard-soft nature of metals on biological interaction, heteroleptic compounds [FeII(L1)(L2)](1) and [FeIII(L1)(L2)]Cl (2) were prepared where ligands are (2-hydroxy-1-naphthylidene-o-aminophenol) [L1] and 1,10-phenanthroline [L2]. Complexes are characterized by Fourier transform infrared spectra (FTIR), high resolution mass spectrometry (HRMS), and UV-vis spectroscopic techniques. Square pyramidal geometry of the complex 1 was determined using computational study [density functional theory (DFT) function (B3LYP/ LANL2DZ)]. The characteristic Fe(II) to Fe (III) oxidation and Fe(III) to Fe(II) reduction peaks were observed in the desired potential range for complexes 1 and 2, respectively. Iron complexes demonstrated anticancer effective hydrolytic DNA cleavage efficacy and efficient groove binding prosperity toward DNA with intrinsic and apparent binding constant values of the order of 105  M-1. The complexes displayed good binding capabilities to carrier protein bovine serum albumin (BSA). The experimental DNA and BSA binding nature was validated through molecular docking study. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET)drug screening profiling indicates that complex 1 satisfies all of Lipinski rule with good cell permeability, solubility, lipophilicity, and nontoxicity. Complexes show efficient anticancer activity in MCF-7 cell lines through apoptotic pathway. Complex 1 is found to have better biological activity compared to 2 due to softer nature of Fe(II) ion.

Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes, lacking targeted therapies and exhibiting elevated levels of intracellular Cu2+ ions. Smart multifunctional nanocarriers capable of dual drug-gene delivery offer a promising strategy for improved TNBC management. In this study, we present an injectable, triple-stimuli-responsive polymeric nanocarrier engineered via reversible addition-fragmentation chain-transfer (RAFT) polymerization for targeted TNBC theranostics. The amphiphilic triblock copolymer integrates three functional components: a photochromic spiropyran (SP) unit enabling light responsiveness, a pH-sensitive cationic hydroxyethyl methacrylate-glycine (HEMA-Gly) segment facilitating nucleic acid complexation, and a temperature-responsive N-isopropylacrylamide (NIPAAM) unit enabling thermally triggered behavior. Notably, the nanocarrier shows strong fluorescence quenching in the presence of Cu2+ ionsoverexpressed in TNBCsupporting selective cellular recognition. Doxorubicin (DOX) loading and release studies demonstrated controlled, sustained release under mildly acidic conditions mimicking the tumor microenvironment. In vitro evaluations using MDA-MB-231 TNBC cells confirmed the platform's multifunctionality. Cytotoxicity assays indicated biocompatibility, while fluorescence imaging revealed efficient cellular uptake of DOX-loaded micelles. Furthermore, the system modulated cell cycle progression and significantly enhanced intracellular and mitochondrial reactive oxygen species (ROS) production, indicating the potential to induce ROS-mediated apoptosis. Gene delivery experiments showed high transfection efficiency of nucleic acid-loaded micelles, attributed to the cationic HEMA-Gly block. Additionally, intracellular quenching studies confirmed the polymer's selective sensitivity toward TNBC-associated Cu2+ ions. Overall, the RAFT-synthesized triblock copolymer represents a versatile theranostic platform capable of simultaneous drug release, gene transfection, ROS induction, and Cu2+-guided TNBC detection. Its targeted responsiveness and multifunctional performance highlight its promise for advanced TNBC diagnostics and combination therapy.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer, with limited treatment options due to the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) expression. This characteristic renders TNBC resistant to hormone-based and HER2-targeted therapies, leaving cytotoxic chemotherapy as the predominant strategy and highlighting the urgency for novel interventions. In this study, we investigated the mechanism of action of GL24, a potent 4-(phenylsulfonyl)morpholine-based small molecule with selective tumor suppression effects on metastatic TNBC cells, while being ineffective against TNBC cells derived from the primary tumor site, using gene co-expression analysis. By considering the distinct phenotypic responses induced by GL24, we tailored our co-expression analysis approach, selecting gene pairs that exhibited differential co-expression in effective cells while excluding gene pairs that also showed differential patterns in non-effective cells. Constructing a co-expression network from these differential pairs, followed by enrichment analysis and functional annotation, revealed specific gene interactions and molecular pathways associated with GL24-mediated TNBC inhibition. These insights supported the previously established findings that showed convergence on apoptosis based on differentially expressed genes, while also providing complementary information by highlighting pathways involved in metabolic alterations, proliferation, and migration or invasion. This expanded understanding advances the knowledge of the mechanisms of GL24 in combating TNBC.

The phenolic compound profile of ethanolic extract of Stropharia inuncta (Fr.) Quél., a natural macrofungus species, and the effects of this chemical structure on antioxidant, anticholinesterase and antiproliferative activities were evaluated. Antioxidant capacity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and Rel Assay Diagnostics kits; DPPH: 72.653 ± 1.857 mg Trolox equivalents (TE)/g, FRAP: 86.873 ± 1.125 mg TE/g, otal antioxidant status (TAS): 4.049 ± 0.057 mmol/L, total oxidant status (TOS): 9.642 ± 0.038 μmol/L, oxidative stress index (OSI): 0.238 ± 0.002, respectively. Within the scope of anticholinesterase activity, IC50 values of the extract on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes were determined as 55.007 ± 1.411 μg/mL and 82.993 ± 1.501 μg/mL, respectively. Antiproliferative effect was evaluated on A549 human lung adenocarcinoma cell line after 24 h of incubation; significant decrease in cell viability was observed especially at concentrations of 100 and 200 μg/mL. Phenolic content was analyzed by LC-MS/MS method and the highest levels of gallic acid (3713.45 ± 12.26 mg/kg), quercetin (2911.40 ± 6.19 mg/kg), and 4-hydroxybenzoic acid (2167.69 ± 4.71 mg/kg) were detected. Also compounds such as vanillic acid, catechinhydrate and acetohydroxamic acid were found at significant levels. The findings show that S. inuncta is a rich natural source of phenolic compounds and this chemical structure contributes to versatile biological activities. The limited information in the literature on the biological activities and phenolic compound profile of this species positions the study as a contribution to the field.

Hepatocellular carcinoma (HCC) poses a significant global public health challenge, with conventional therapies often limited by severe adverse reactions. This study utilized network pharmacology and molecular docking to identify anti-HCC compounds from Ganoderma applanatum triterpenoids (GAT). Sixty compounds were screened using Swiss ADME, with potential targets predicted subsequently. Intersection analysis with HCC-associated targets identified 339 overlapping targets. Subsequent protein-protein interaction (PPI) network analysis identified nine core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses demonstrated that GAT inhibits HCC progression by modulating cancer-associated signaling pathways such as PI3K-Akt, MAPK, Ras, and Rap1 signaling. A compound-target network identified core compounds. Molecular docking demonstrated strong binding affinities between four compounds (applanaic acid C, methyl gibbosate A, bovistol, lucidone A) and three targets (AKT1, MAPK1, SRC). Toxicity predictions indicated low acute oral toxicity for applanaic acid C (LD50 > 300 mg/kg) and lucidone A (LD50 > 5000 mg/kg). Moreover, immunotoxicity risks were noted, which require key attention during subsequent drug development. This study systematically elucidates the multi-target and multi-pathway anti-HCC mechanisms of GAT providing a foundation for developing natural product-derived therapeutics. Further experimental validation of the efficacy and safety profiles is warranted for these potential lead compounds.

Glioblastoma (GBM) is one of the most aggressive and treatment-refractory brain tumors. Temozolomide (TMZ) remains the standard chemotherapeutic agent but is frequently compromised by DNA-repair mechanisms, whereas tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis only in a subset of tumors due to strong intrinsic resistance. Here, we identify the Mu-2-related death-inducing gene (MUDENG/MuD) as the µ-subunit of adaptor protein complex 5 (AP5M1). TurboID-based proximity labeling revealed reproducible interactions with AP5B1 and AP5M1 subunits, as well as additional associations with AP1-3 complexes and nuclear proteins involved in cell-cycle regulation. These findings establish MuD as a multifunctional component of the AP5 complex that modulates cell-fate signaling in a context-dependent manner. Using MuD-mutant GBM cell lines, we demonstrate that MuD suppresses TRAIL-induced apoptosis by interfering with extrinsic and intrinsic pathways downstream of Bid, whereas it promotes TMZ-induced cytotoxicity through p53-dependent cell-cycle control and DNA-damage responses. Gene set enrichment analysis (GSEA) and functional profiling further revealed distinct MuD-associated interactomes linked to receptor endocytosis and genotoxic-stress pathways. Together, these results uncover opposing roles of MuD in TRAIL- and TMZ-mediated cell death, with MuD suppressing apoptotic signaling in response to TRAIL while modulating p53-dependent genotoxic stress responses that influence TMZ-induced cytotoxicity in glioblastoma.

While anti-programmed death-1 (anti-PD-1) therapy has revolutionized lung cancer treatment, its efficacy remains limited by an immunosuppressive tumor microenvironment (TME). We therefore investigated whether combining anti-PD-1 inhibitor with catgut embedding at the Zusanli acupoint (CIAA) could enhance anti-tumor immunity by reprogramming the TME in a lung cancer mouse model. Combining in vivo tumor monitoring, multi-parametric immune profiling (flow cytometry, IHC, ELISA), and multi-omics analyses (transcriptomics and metabolomics), we found that the combination therapy was associated with enhanced tumor growth inhibition. This effect correlated with a comprehensive TME transformation: conversion to an immunologically active state with increased effector immune cell infiltration (CD8⁺ T, CD4⁺ T, B cells, macrophages) and decreased regulatory T cells, coupled with suppression of pro-tumorigenic factors (VEGF, IL-6). Integrated omics analysis suggests that the combined treatment may modulate tumor-stroma interaction pathways (e.g., PI3K-Akt, focal adhesion) and rewire immunometabolic networks (e.g., tryptophan metabolism). Our study provides hypothesis-generating correlative data positioning CIAA as a potential adjunct capable of remodeling the TME to potentiate anti-PD-1 therapy in lung cancer.

Triple-negative breast cancer (TNBC) treatment with traditional phototherapeutics generally suffers from short light penetration depth and limitations of the hypoxic tumor microenvironment. Developing effective therapeutic modalities tailored to TNBC's features remains highly desirable yet challenging. Herein, we propose a near-infrared dual windows (NIR-II) photoacoustic (PA) cavitation-based strategy to amplify oxidative stress and induce metabolic disruption in TNBC cells, achieving effective tumor suppression. With a fabricated nanoagent (DTG), we integrated the oxygen-independent therapeutic effects of photomechanical damage, cavitation-promoted oxidative damage and glucose oxidase (GOx)-mediated glucose depletion. Specifically, under NIR-II pulsed laser (PL) irradiation, PA cavitation generates collapsing bubbles and shock waves, causing mechanical injury to tumor cells. Meanwhile, GOx depletes intratumoral glucose, blocking glycolysis, reducing adenosine triphosphate (ATP) production, and generating hydrogen peroxide (H2O2) that would be further converted into more toxic hydroxyl radicals (•OH) by the photocavitation to suppress the tumors effectively. In addition, the strong NIR-II PA signal produced from the DTG facilitates high-resolution deep-tissue imaging to provide precise therapeutic guidance. Thus, these findings establish the multimodal strategy as a potent candidate for TNBC management.

A growing number of malignancies have shown favorable responses to immune checkpoint inhibitors (ICI), most commonly anti-PD-(L)1 antibodies. However, prostate cancer has been associated with mostly unfavorable responses to ICI. This review discusses various trials related to PD-(L)1 inhibitors in prostate cancer.

To develop a predictive model for paclitaxel (PTX)-induced moderate-to-severe myelosuppression in hospitalized cancer patients and to evaluate its accuracy through cross-validation.

The aim of the present study was to investigate the prevalence of oral manifestations among patients undergoing chemotherapy.

Camptothecin (CPT) is a highly potent antitumor agent; however, it exhibits severe systemic toxicity in clinical application. Herein, we utilized the endogenous molecule oxidized glutathione (GSSG) as a carrier for CPT delivery, aiming to circumvent both the accumulative toxicity of the carrier and the systemic toxicity of the drug. Poly-GSSG was conjugated with CPT to develop a glutathione-responsive nanomedicine (Poly GSSG-CPT). The structure of Poly GSSG-CPT was confirmed via FT-IR, NMR, and MALDI-TOF analyses. The cumulative CPT release rate from Poly GSSG-CPT reached 97.9% after 120 h in a 10 mg mL-1 glutathione (GSH) environment, as measured by UV-vis spectroscopy. CCK-8 assays and flow cytometry experiments demonstrated that Poly GSSG-CPT and CPT exhibited comparable cytotoxic effects against HeLa cells. Furthermore, confocal laser scanning microscopy (CLSM) and in vivo imaging (IVIS) showed that Poly GSSG-CPT could be localized in cell nuclei within 6 h and accumulated in tumor tissue within 48 h. Studies using tumor-bearing mice and histopathological analyses confirmed that Poly GSSG-CPT significantly enhanced antitumor efficacy and reduced systemic toxicity. Altogether, the Poly GSSG-CPT nanomedicine based on GSSG and CPT showed superior stability in an aqueous environment, greater tumor inhibition ability, and fewer side effects in vivo. This work demonstrates that endogenous molecules used as carriers may represent a promising strategy for developing nanomedicine with higher therapeutic efficacy and lower systemic toxicity.