Experimental Hematology & Oncology最新文献

{"title":"Intratumoral microbiota in cancer immunotherapy: metabolic-epigenetic crosstalk and engineered bacterial therapeutics.","authors":"Niying Zhao, Huan Zhang, Yutong Pang, Lingqin Zhu, Qinghua Liu, Zhiya Zhang, Lin Shen, Yuqi He, Shuye Lin","doi":"10.1186/s40164-026-00840-x","DOIUrl":"10.1186/s40164-026-00840-x","url":null,"abstract":"<p><p>The intratumoral microbiome critically influences immunotherapy efficacy by modulating the host immune microenvironment and epigenetic landscape through its metabolites. Microbial derived metabolites such as short chain fatty acids, secondary bile acids, trimethylamine N oxide, and tryptophan derivatives reprogram host cell epigenetics via DNA methylation, histone modifications, and non-coding RNAs, thereby shaping anti-tumor immunity and driving either immune activation or resistance. In turn, the hypoxic, acidic, and nutrient deprived tumor microenvironment reshapes microbial composition and metabolism, forming a vicious cycle that further affects therapeutic outcomes. Given these pivotal roles, targeting the intratumoral microbiota has emerged as a promising strategy. Advances in synthetic biology have enabled the development of engineered bacteria as programmable living therapeutics. These engineered strains achieve tumor specific colonization, controlled drug release, and multimodal functions such as cytokine secretion, immune checkpoint blockade, STING pathway activation, and metabolic reprogramming. By enhancing immune checkpoint inhibitor efficacy and synergizing with cell therapies, engineered bacterial therapy represents a highly promising approach to improve immunotherapy efficiency. Despite challenges in clinical translation including heterogeneity, anti-vector immunity, and manufacturing complexity, this strategy offers a new paradigm for precision cancer treatment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venetoclax-based combinations in high-risk myelodysplastic syndromes: highlights from ASH 2025 & EHA 2026.","authors":"Ines Zugasti, Marina Cornejo, Sandra Castaño-Diez, Juan Jose Rodriguez-Sevilla, Albert Cortes-Bullich, Jordi Esteve, Marina Diaz-Beya","doi":"10.1186/s40164-026-00832-x","DOIUrl":"10.1186/s40164-026-00832-x","url":null,"abstract":"<p><p>High-risk myelodysplastic syndromes (HR-MDS) are associated with poor survival despite standard therapy with hypomethylating agents (HMAs). Although the VERONA trial did not meet its primary endpoint, a granular interpretation of these results alongside real-life data may help identify patient subsets that could potentially benefit. At the 2025 American Society of Hematology (ASH) Meeting and at the 2026 European Hematology Association Congress (EHA), several studies reported updated data on venetoclax-based combinations in HR-MDS across clinical and biological subgroups. The randomized phase III VERONA study evaluated venetoclax plus azacitidine (VEN/HMA) versus azacitidine alone in the frontline setting, while additional phase I/II and real-life studies explored oral hypomethylating backbones, therapy-related disease, and molecularly defined subsets. Collectively, these data suggest that venetoclax enhances response rates in HR-MDS, although survival benefits remain heterogeneous, with a potential benefit observed when used as a bridge to transplantation. Given the lack of randomized data in transplant-eligible patients, this Correspondence provides a narrative, non-systematic review of the available evidence based mostly on abstracts and not peer reviewed publications. Additionally, we summarize the most clinically relevant findings and discuss their implications for future treatment strategies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming in cancer-associated fibroblasts: orchestrating the tumor immune microenvironment and response to immune checkpoint blockade.","authors":"Luoman Gan, Zhonglong Liu, Liren Cao, Xiaoyan Meng, Xuanhao Liu, Xu Wang, Yue He","doi":"10.1186/s40164-026-00837-6","DOIUrl":"https://doi.org/10.1186/s40164-026-00837-6","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) has reshaped the therapeutic landscape of solid tumors. However, durable clinical benefit remains limited to a subset of patients because of primary or acquired resistance. Beyond tumor-intrinsic factors, the tumor microenvironment (TME) plays a critical role in shaping responsiveness to immunotherapy. As a major stromal component, cancer-associated fibroblasts (CAFs) contribute to immune suppression through dynamic metabolic reprogramming and modulate the spatial organization and functional state of immune cells. Recent advances in single-cell transcriptomics, spatial omics, and metabolomic profiling have provided new insights into the metabolic heterogeneity of CAF subsets and their interactions with immune cells. Metabolic reprogramming not only sustains CAF activation but also remodels the local immune environment through nutrient competition, metabolite accumulation, and coordination with extracellular matrix remodeling. These processes reinforce immunosuppression within the TME and contribute to resistance to ICB. This review integrates emerging multi-omics insights into CAF metabolic heterogeneity, summarizes how metabolic reprogramming shapes tumor immunity, and discusses therapeutic strategies targeting CAF metabolism to enhance immunotherapy efficacy, together with the major challenges facing clinical translation.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond MYD88-only testing: MYD88/CD79B profiling improves molecular detection and MCD genotyping in VRL and CNS lymphomas.","authors":"Mona M Wang, Yuanhan Li, Gee Fung How, Candice E H Ho, Nagavalli DO Somasundaram, Jason Yongsheng Chan, Timothy Kwang Yong Tay, Than Hein, Anita Sook Yee Chan","doi":"10.1186/s40164-026-00836-7","DOIUrl":"10.1186/s40164-026-00836-7","url":null,"abstract":"<p><p>Diagnosing rare, aggressive immune-privileged (IP)-large B-cell lymphomas (LBCL), such as primary vitreoretinal lymphoma (VRL) and primary central nervous system lymphoma (CNSL), remains challenging due to the fragility of lymphoma cells within the vitreous or cerebrospinal fluid (CSF) and paucicellular yields, which preclude definitive cytological diagnosis. Clinical MYD88^L265P testing has therefore been incorporated into many haematology diagnostic workflows. These gel-based AS-PCRs are limited by DNA input and quality, are restricted to predefined hotspot variants, and cannot detect CD79B ITAM domain variants, which are seen in IP-LBCLs with MYD88/CD79B (MCD) genotype. To address these limitations, we developed a low-input multiplex MYD88/CD79B PCR and Sanger sequencing workflow that detects canonical MYD88 mutations and additional TIR-domain variants, along with CD79B ITAM-domain mutations, and evaluated its clinical performance in 42 vitreous specimens and 4 CSF specimens. Paired validation with clinical VRL and known inflammatory biopsies (N = 46) showed higher sensitivity, specificity, and diagnostic accuracy of 81.8%,100%, and 94.7%, respectively, over the current standard of care MYD88^L265P laboratory-developed test (LDT) whilst reducing the minimum DNA input from 1ng to 0.016 ng and maintaining diagnostic concordance with LDT, clinical findings, and whole-exome sequencing (WES). Mixed wild-type and mutant Sanger sequencing peak patterns also provided insight into mutational burden and tumour heterogeneity. Although WES remains more comprehensive, multiplex MYD88/CD79B PCR with sequencing represents a practical intermediate molecular strategy for molecular characterization, identification of the MYD88/CD79B-associated (MCD) genotype, and support for therapeutic and prognostic assessment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting adaptive EGFR feedback enhances the therapeutic efficacy of RMC-6236 in cholangiocarcinoma.","authors":"Shiori Yamazaki, Nao Hondo, Koya Yasukawa, Masato Kitazawa, Satoshi Nakamura, Yuta Yamamoto, Satoru Miyazaki, Hirokazu Tanaka, Masatsugu Kuroiwa, Naoki Ishizaka, Tadaaki Shimizu, Akira Shimizu, Yuji Soejima","doi":"10.1186/s40164-026-00835-8","DOIUrl":"https://doi.org/10.1186/s40164-026-00835-8","url":null,"abstract":"<p><strong>Background: </strong>Approximately 20% of cholangiocarcinomas harbor KRAS mutations, with codon 12 variants accounting for most of the cases. Among these, G12V is associated with a poor prognosis, whereas G12D is the most frequent subtype. RMC-6236, a novel RAS (ON) multi-selective inhibitor targeting multiple KRAS codon 12 mutations, has shown promise in early clinical studies in KRAS-mutant cholangiocarcinomas.</p><p><strong>Methods: </strong>We evaluated the therapeutic efficacy of the novel RAS (ON) inhibitor RMC-6236 as a monotherapy and in combination with gemcitabine and the anti-EGFR antibody cetuximab in KRAS-mutant cholangiocarcinoma (CCA) models. Antitumor activity and signaling alterations were assessed using in vitro cell-based assays, western blot analysis, and in vivo xenograft models.</p><p><strong>Results: </strong>RMC-6236 potently inhibited cell proliferation in KRAS-mutant (G12D and G12V) cell lines at nanomolar concentrations (10-30 nM) and effectively suppressed pERK signaling. Notably, RMC-6236 treatment was accompanied by increased pEGFR expression, indicating adaptive EGFR feedback activation as a potential mechanism of resistance. In vitro, combination treatments significantly enhanced growth inhibition compared with monotherapy. In xenograft models, RMC-6236 treatment induced dose-dependent tumor regression, whereas combination with cetuximab or gemcitabine further enhanced the antitumor efficacy.</p><p><strong>Conclusion: </strong>EGFR-mediated feedback represents a targetable vulnerability in KRAS-mutant cholangiocarcinomas. Targeting EGFR signaling attenuates adaptive feedback reactivation induced by pan-RAS (ON) inhibition and supports the clinical development of combination strategies with EGFR blockade or cytotoxic chemotherapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation CAR-T therapy for malignant brain tumors: latest updates from the 2026 AACR Annual Meeting.","authors":"Valbert Oliveira Costa Filho, Silvia Helena Barem Rabenhorst, Felipe Pantoja Mesquita","doi":"10.1186/s40164-026-00834-9","DOIUrl":"10.1186/s40164-026-00834-9","url":null,"abstract":"<p><p>The 2026 AACR Annual Meeting showcased rapid progress in chimeric antigen receptor (CAR) T-cell therapy for malignant brain tumors. This correspondence synthesizes 12 clinical and translational abstracts addressing early efficacy, resistance mechanisms, target discovery, and next-generation engineering. Phase I studies in glioblastoma demonstrated feasibility, manageable toxicity, cellular persistence, and preliminary radiographic activity, while revealing antigen loss and treatment-associated myeloid suppression. Longitudinal and spatial analyses further identified limited CAR T-cell persistence, anti-CAR immune responses, and remodeling of suppressive tumor niches. Preclinical strategies sought to overcome these barriers through programmable antigen recognition, alternative KIR/DAP12 signaling, stress-granule modulation, inducible metabolic support, membrane-tethered cytokine agonists, resistance to transforming growth factor beta, and dual targeting of tumor cells and immunosuppressive macrophages. Surfaceome profiling and affinity-guided receptor optimization also identified promising targets in glioblastoma and medulloblastoma. Collectively, these findings support mechanism-informed CAR T-cell platforms, while emphasizing that durability, neurotoxicity, trafficking, immunogenicity, and patient selection require validation in larger clinical studies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daraxonrasib and the era of pan-RAS inhibition: mechanisms, clinical advances, and resistance landscapes.","authors":"Jiacheng Lou, Danlu Zhang","doi":"10.1186/s40164-026-00833-w","DOIUrl":"10.1186/s40164-026-00833-w","url":null,"abstract":"<p><p>Activating RAS mutations drive a substantial proportion of human cancers, yet for decades RAS was considered undruggable. The recent development of tri-complex inhibitors (TCIs) such as daraxonrasib (RMC-6236) has transformed the therapeutic landscape by enabling potent, multi-selective targeting of the active, GTP-bound state of multiple RAS isoforms. This review synthesizes preclinical and clinical evidence on daraxonrasib and related RAS(ON) inhibitors across RAS-mutant malignancies, including pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, melanoma, and cholangiocarcinoma. We examine the structural basis of TCI action, pharmacokinetic considerations, and the profound tumor regressions observed in early-phase trials, including the unprecedented overall survival benefit in PDAC. A central focus is the emergence of resistance through diverse mechanisms: acquired mutations in CYPA, RAS, and BRAF that disrupt drug-target complex formation or restore RAS-RAF signaling; adaptive rewiring via mTORC1, STAT3, and cell cycle pathways; and tumor microenvironment-mediated resistance. We further explore rational combination strategies designed to forestall resistance, including vertical MAPK pathway blockade, orthogonal inhibition of EGFR/STAT3, CDK4/6 targeting, and immunotherapy combinations that leverage RAS inhibition-induced immune priming. By integrating structural biology, translational pharmacology, and clinical outcomes, this review provides a comprehensive framework for understanding the promise and challenges of pan-RAS inhibition in precision oncology.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of haploidentical, matched sibling and matched unrelated donor allo-HCT in adult patients with AML in complete remission with measurable residual disease: a study from the Global committee and the ALWP of the EBMT.","authors":"Yishan Ye, Jacques-Emmanuel Galimard, Myriam Labopin, Francis Ayuk, Ibrahim Yakoub-Agha, Matthias Stelljes, Urpu Salmenniemi, Thomas Schroeder, Gesine Bug, Maria-Pilar Gallego-Hernanz, Edouard Forcade, Jakob Passweg, Maija Itala-Remes, Simona Piemontese, Jaime Sanz, Ali Bazarbachi, Arnon Nagler, Eolia Brissot, Lin Li, Yi Luo, Jimin Shi, Yanmin Zhao, Mohamad Mohty, He Huang, Fabio Ciceri, Norbert Claude Gorin","doi":"10.1186/s40164-026-00827-8","DOIUrl":"10.1186/s40164-026-00827-8","url":null,"abstract":"","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated KMT2D mutant targeting immunogenic rewiring to overcome epigenetic entropy promotes follicular lymphomagenesis.","authors":"Yuqian Zhu, Jingwei Yao, Yuelong Jiang, Qian Lai, Qinwei Chen, Jingxing Zhang, Manman Deng, Zhijuan Lin, Yiming Luo, Zhifeng Li, Long Liu, Zhong Zheng, Jie Zha, Bing Xu","doi":"10.1186/s40164-026-00829-6","DOIUrl":"10.1186/s40164-026-00829-6","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic modifier factors in B cell lymphomas often harbor loss-of-function mutations. Mutations occurring in the histone-lysine methyltransferase 2D (KMT2D) gene are the pivotal chromatin-modifying hallmarks of follicular lymphoma (FL) subsets, however their tumor-promoting roles are unclear.</p><p><strong>Methods: </strong>Targeted sequencing was employed to evaluate a core panel of genes implicated in histone methylation (EZH2, KMT2D), histone acetylation (CREBBP, EP300), and chromatin remodeling (ARID1A, BCL7A) in FL patients. Functional characterization of the KMT2D mutation (KMT2D^mut) was carried out in vitro. RNA sequencing analysis was utilized to identify differentially expressed genes (DEGs) and significantly enriched pathways. The role of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) in mediating the function of the KMT2D^mut was investigated in B-lymphoma cell models using lentivirus. Through transcriptome deconvolution, integrative analyses combining chromatin immunoprecipitation and genome-wide chromatin accessibility were performed in KMT2D-mutant cell lines. Additionally, chromatin immunoprecipitation, immunofluorescence assays, and immunoblotting analyses were conducted.</p><p><strong>Results: </strong>KMT2D mutations were the most frequent genetic alterations in FL (63%), predominantly consisting of nonsense and frameshift variants. Compared with wild-type, KMT2D-mutant FL exhibited markedly reduced H3K9me3 levels and increased chromatin accessibility at distal regulatory regions. Functionally, KMT2D^mut promoted proliferation, suppressed apoptosis, and arrested cells in G2 phase. In FL, mutant KMT2D suppressed H3K9 methylation, leading to ALDH1A1 upregulation and the emergence of a highly plastic B‑cell state, followed by ATP7A overexpression, which ultimately reshaped the immune microenvironment.</p><p><strong>Conclusions: </strong>KMT2D^mut drives FL progression by relieving H3K9me3-mediated epigenetic modification, activating PDK1/SGK1 signaling and an ALDH1A1-driven stemness program, and upregulating ATP7A to rewire copper homeostasis and redox balance. Our findings delineate a central molecular network through which KMT2D^mut operates in FL and provide a mechanistic rationale for therapeutic targeting of KMT2D.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of PARPi and topoisomerase I inhibitors is highly effective in olaparib-resistant ovarian cancer.","authors":"M Chiappa, V Villa, F Sias, C Grasselli, L Sala, S Canesi, M Marabese, S Mason, D Dibitetto, R Fruscio, G Damia","doi":"10.1186/s40164-026-00828-7","DOIUrl":"10.1186/s40164-026-00828-7","url":null,"abstract":"<p><p>High-grade serous ovarian carcinoma (HGSOC) often shows an initial response to poly (ADP-ribose) polymerase inhibitors (PARPi) such as olaparib, particularly in tumors with defects in homologous recombination (HR), but resistance to these drugs is a major clinical challenge. To address this, we screened over 1400 FDA-approved compounds to find agents that could restore olaparib sensitivity in resistant ovarian cancer cells. DNA topoisomerase I inhibitors (TOP1i) emerged as the most effective partner. The combination of TOP1 inhibitors with PARPi showed strong synergistic anticancer effects across multiple murine and human HGSOC models, regardless of HR status, including patient-derived xenografts made resistant to olaparib. The combination was well tolerated and primarily worked by inducing apoptosis and increased DNA damage. These findings suggest that TOP1 inhibitors combined with PARP inhibitors could be a promising treatment strategy for olaparib-resistant ovarian cancer.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}