Journal of Hematology & Oncology最新文献

{"title":"A multicenter, open-label, single-arm, phase Ib clinical trial of HH2853 treatment in patients with relapsed and/or refractory peripheral T-cell lymphoma","authors":"Huangming Hong, Zegeng Chen, Mingzhi Zhang, Zhigang Peng, Jianzhen Shen, Yuerong Shuang, Hui Zhou, Hongqiang Guo, He Huang, Fei Li, Zhengzi Qian, Lihong Liu, Liang Wang, Wei Yang, Liling Zhang, Pengcheng He, Shen Qian, Fugen Li, Meng Li, Tongyu Lin","doi":"10.1186/s13045-025-01697-z","DOIUrl":"https://doi.org/10.1186/s13045-025-01697-z","url":null,"abstract":"Peripheral T-cell lymphoma (PTCL) is an aggressive malignancy with limited treatment options and poor prognosis, particularly for relapsed or refractory (r/r) patients. HH2853, a novel dual inhibitor of EZH1/2, has previously demonstrated clinical benefits in solid tumors. Here, we report safety and efficacy data from a phase Ib trial of HH2853 in r/r PTCL. A phase Ib clinical trial in PTCL was conducted from July 2022–August 2023 at 15 sites in China. The study employed a dose-escalation phase (300 mg, 400 mg, and 600 mg BID) to determine the recommended phase II dosage (RP2D), followed by a dose expansion phase (300 mg and 400 mg BID). The primary endpoints were safety and the overall response rate (ORR). Thirty-four patients with various r/r PTCL histology types, a median age of 58 years, and a median of 2 prior systemic therapies were enrolled. Treatment-related adverse events (TRAEs) were observed in 92.1% of the patients, with 20.6% experiencing grade 3 TRAEs. The most common TRAEs included anemia (67.6%), thrombocytopenia (52.9%), leukopenia (44.1%), and diarrhea (38.2%). One patient (2.9%) receiving 600 mg BID experienced dose-limiting toxicity due to grade 4 thrombocytopenia. The dose of 400 mg BID was selected as the RP2D. The ORR was 67.6%, comprising 29.4% complete remission and 38.2% partial remission. As of the data cutoff in September 2024, the median follow-up period was 15.7 months, with a median duration of response of 14.8 months; overall survival had not yet been reached. The selective EZH1/2 dual inhibitor HH2853 demonstrated acceptable and manageable safety profiles and promising efficacy in r/r PTCL patients, indicating its therapeutic potential for this difficult-to-treat patient population. NCT04390737","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"17 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The cGAS‒STING pathway in cancer immunity: mechanisms, challenges, and therapeutic implications","authors":"Mengzhou Shen, Xianjie Jiang, Qiu Peng, Linda Oyang, Zongyao Ren, Jiewen Wang, Mingjing Peng, Yujuan Zhou, Xiyun Deng, Qianjin Liao","doi":"10.1186/s13045-025-01706-1","DOIUrl":"https://doi.org/10.1186/s13045-025-01706-1","url":null,"abstract":"<p><b>Correction: Journal of Hematology & Oncology (2025) 18:40</b></p><p><b>https://doi.org/10.1186/s13045-025-01691-5</b></p><p>The original article has been updated to restore Qianjin Liao to Corresponding Authorship.</p><span>Author notes</span><ol><li><p>Mengzhou Shen and Xianjie Jiang contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Oncology, Hunan Provincial People’s Hospital and The First Affiliated Hospital of Hunan Normal University, Hunan Normal University Health Science Center, Changsha, Hunan, 410005, China</p><p>Mengzhou Shen, Jiewen Wang & Qianjin Liao</p></li><li><p>The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Key Laboratory of Cancer Metabolism, Central South University, Hunan Cancer Hospital, Changsha, Hunan, 410013, China</p><p>Mengzhou Shen, Xianjie Jiang, Qiu Peng, Linda Oyang, Zongyao Ren, Jiewen Wang, Mingjing Peng & Yujuan Zhou</p></li><li><p>School of Basic Medical Sciences, Hunan Normal University, Changsha, Hunan, 410013, China</p><p>Xiyun Deng</p></li><li><p>Hunan Engineering Research Center of Tumor Organoid Technology and Application, Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, 410013, China</p><p>Yujuan Zhou & Qianjin Liao</p></li></ol><span>Authors</span><ol><li><span>Mengzhou Shen</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xianjie Jiang</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Qiu Peng</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Linda Oyang</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Zongyao Ren</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Jiewen Wang</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Mingjing Peng</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yujuan Zhou</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiyun Deng</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Qianjin Liao</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding authors</h3><p>Corresp","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"7 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PFS24 as a prognostic milestone in patients with newly diagnosed primary CNS lymphoma","authors":"Vanja Zeremski, Tobias R. Haage, Hanno M. Witte, Louisa Adolph, Sina A. Beer, Gerhard Behre, Benedikt Jacobs, Christoph Kahl, Chrysavgi Lalayanni, Jens Panse, Sotirios Papageorgiou, Marina P. Siakantaris, Jessica Schneider, Ulf Schnetzke, Alexander Schulz, Theodoros P. Vassilakopoulos, Jeanette Walter, Dimitrios Mougiakakos","doi":"10.1186/s13045-025-01700-7","DOIUrl":"https://doi.org/10.1186/s13045-025-01700-7","url":null,"abstract":"High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has significantly improved overall survival (OS) in primary central nervous system lymphoma (PCNSL). However, early identification of long-term survivors remains a challenge. Progression-free survival at 24 months (PFS24) has emerged as a key prognostic marker in diffuse large B-cell lymphoma, but its relevance in PCNSL is still unclear. In this retrospective multicenter study, we analyzed data from 146 newly diagnosed, transplant-eligible PCNSL patients treated with MATRix-like regimens across 14 hospitals. With a median follow-up of 48 months, the 2-year PFS and OS rates were 50.4% and 65.6%, respectively. Of the 139 patients evaluable for PFS24-analysis, 51.1% reached PFS24, with a subsequent 5-year OS of 96.7%. Of note, the annual hazard rate for progression and death decreased to under 5% after 24 months, remaining stable thereafter. The patients who failed to reach PFS24 had a median OS of only 6.0 months. Key predictors of PFS failure included impaired Karnofsky performance status and treatment dose-reduction. In conclusion, PFS24 was identified as an important prognostic marker in PCNSL. Patients who achieve PFS24 have a favorable prognosis, whereas those who do not face poor outcomes and require innovative treatment approaches. This insight could aid in risk stratification and support the use of PFS24 as a surrogate endpoint in clinical trials.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"24 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD20 xCD3 bispecific antibodies for large B cell lymphoma: latest updates from 2024 ASH annual meeting","authors":"V. Tomarchio, L. Rigacci, O. Annibali","doi":"10.1186/s13045-025-01695-1","DOIUrl":"https://doi.org/10.1186/s13045-025-01695-1","url":null,"abstract":"Bispecific antibodies (BsAbs) represent an innovative class of off-the-shelf T-cell redirecting agents and are considered among the most promising immunotherapeutic strategies for the treatment of lymphoma. Notably, anti-CD20 × CD3 BsAbs have exhibited substantial monotherapy efficacy in patients with heavily pretreated B-cell non-Hodgkin lymphoma (B-NHL), showing a tolerable toxicity profile predominantly associated with T-cell activation-related side effects. In this study, we summarized several latest reports on CD20 × CD3 bsAbs for the therapy of Large B Cell Lymphoma (LBCL), also in first line, from the ASH 2024 annual meeting (ASH 2024).","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"71 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial imaging unlocks the potential of charting multiple myeloma and extramedullary disease","authors":"Vanessa Desantis, Alessandro Andriano, Tim Düking, Olga Hartwig, Giuseppe Ingravallo, Marta Biondo, Cirino Botta, Roberto Ria, Angelo Vacca, Antonio Giovanni Solimando","doi":"10.1186/s13045-025-01699-x","DOIUrl":"https://doi.org/10.1186/s13045-025-01699-x","url":null,"abstract":"Extramedullary disease (EMD) in multiple myeloma (MM) represents a significant clinical challenge, with a limited understanding of the spatial architecture and its pathobiological impact. To address this unmet need, we examined 10 matched samples from bone marrow (BM) and cognate EMD sites. This investigation provides critical insights into the distinct features of EMD, offering potential avenues for more effective diagnosis and targeted therapies. To this aim, we employed MACSima™ Imaging Cyclic Staining (MICS) to unveil distinct biomarker expression profiles as companion diagnostics for a personalized therapeutic approach for MM. We observed elevated BCL-2 levels in EMD plasma cells (p < 0.0001), indicating the potential of BCL-2 inhibitors to target anti-apoptotic pathways in select cases. The higher expression of EZH2 in EMD compared to BM (p < 0.0001) highlights its role in sustaining aggressive tumor phenotypes and supports the use of epigenetic-targeting agents in key situations. In contrast, CD3 + T-cell distance was significantly higher in EMD, reflecting impaired immune surveillance (p < 0.0001). Across the cohort, our analysis revealed significant differences between BM and EMD regarding the expression and spatial organization of key markers. CD38 expression was markedly reduced in EMD plasma cells (p < 0.0001). These findings underscore profound biological heterogeneity in MM and its BM emancipated disease phenotype, emphasizing dysfunctional apoptosis, immune evasion and resistance to CD38-targeting therapies in EMD, conceivably informing future validations. By integrating high-dimensional data, this study provides insights into potential druggable vulnerabilities for crafted interventions, particularly challenging in EMD cases.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"24 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Replicon RNA vaccines: design, delivery, and immunogenicity in infectious diseases and cancer","authors":"Lirui Tang, Haiying Que, Yuquan Wei, Ting Yang, Aiping Tong, Xiawei Wei","doi":"10.1186/s13045-025-01694-2","DOIUrl":"https://doi.org/10.1186/s13045-025-01694-2","url":null,"abstract":"Replicon RNA (RepRNA) represents a cutting-edge technology in the field of vaccinology, fundamentally transforming vaccine design and development. This innovative approach facilitates the induction of robust immune responses against a range of infectious diseases and cancers. RepRNA vaccines leverage the inherent capabilities of RNA-dependent RNA polymerase associated with self-replicating repRNA, allowing for extreme replication within host cells. This process enhances antigen production and subsequently stimulates adaptive immunity. Additionally, the generation of double-stranded RNA during RNA replication can activate innate immune responses. Numerous studies have demonstrated that repRNA vaccines elicit potent humoral and cellular immune responses that are broader and more durable than those generated by conventional mRNA vaccines. These significant immune responses have been shown to provide protection in various models for infectious diseases and cancers. This article will explore the design and delivery of RepRNA vaccines, the mechanisms of immune activation, preclinical studies addressing infectious diseases and tumors, and related clinical trials that focus on safety and immunogenicity.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"3 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRAS mutation detection by liquid biopsy for pancreatic ductal adenocarcinoma","authors":"Mahmoud Yousef, Abdelrahman Yousef, Mark W. Hurd, Ashwathy Pillai, Saikat Chowdhury, Rebecca Snyder, Mark Knafl, Ryan L. Lewis, Paul M. Roy, Mohammad Fanaeian, Sali Albarouki, Luca F. Castelnovo, Jennifer Peterson, Brandon G. Smaglo, Robert A. Wolff, Shubham Pant, Jason Willis, Ryan Huey, Michael Overman, Ching-Wei Tzeng, Michael P. Kim, Naruhiko Ikoma, Jess E. Maxwell, Matthew H. G. Katz, Huamin Wang, Anirban Maitra, Eugene Koay, Ethan B. Ludmir, Anthony Chen, Camila Lopez, Haoqiang Ying, John Paul Shen, Dan Zhao","doi":"10.1186/s13045-025-01696-0","DOIUrl":"https://doi.org/10.1186/s13045-025-01696-0","url":null,"abstract":"The clinical utility of liquid biopsy (LB) for pancreatic ductal adenocarcinoma (PDAC) remain understudied. Our single-institution cohort of 311 PDAC patients with non-tumor tissues informed LB found 81.2% positivity (N = 186) in metastatic cases and in 52.4% (N = 43) of localized disease. KRAS mutations were detected in 64.6% (N = 148) of metastatic cases and 16% (N = 13) for localized disease. Positive LB, especially KRAS mutation detection, is associated with worse overall survival (OS) in metastatic PDAC (median 14.5 vs. 31.3 months, HR = 2.7, 95%CI = 1.7–4.3, P < 0.0001). The positive concordance rates of KRAS and TP53 mutations were 63% and 68% in metastatic disease but only 7% (KRAS) and 33% (TP53) in localized disease, respectively. Among the 41 patients who underwent serial liquid biopsy testing, 25% tested positive after an initial negative result. LB detects therapeutically targetable mutations in 58.5% of PDAC patients and is associated with OS.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"60 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanomaterials-driven in situ vaccination: a novel frontier in tumor immunotherapy","authors":"Naimeng Liu, Xiangyu Wang, Zhongzhao Wang, Yonemori Kan, Yi Fang, Jidong Gao, Xiangyi Kong, Jing Wang","doi":"10.1186/s13045-025-01692-4","DOIUrl":"https://doi.org/10.1186/s13045-025-01692-4","url":null,"abstract":"In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a “cold” tumor into a “hot” tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"4 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The current landscape of gastric cancer and gastroesophageal junction cancer diagnosis and treatment in China: a comprehensive nationwide cohort analysis","authors":"Yang Chen, Keren Jia, Yi Xie, Jiajia Yuan, Dan Liu, Lei Jiang, Haoxin Peng, Jia Zhong, Jian Li, Xiaotian Zhang, Lin Shen","doi":"10.1186/s13045-025-01698-y","DOIUrl":"https://doi.org/10.1186/s13045-025-01698-y","url":null,"abstract":"Gastric cancer is the fifth most common cancer globally and is associated with significant morbidity and mortality. Despite its alarming prevalence, limited comparative evidence exists on its treatment efficacy and prognosis across diverse China populations. To address this, our study used a large-scale dataset from the National Cancer Information Database, including data from 220,304 patients from 53 leading hospitals across 27 provinces in China. From 2017 to 2023, early-stage (Stages I-II) gastric cancer diagnoses increased to 35.63% of all cancer cases. Our study evaluated the neoadjuvant treatment strategies, adjuvant post-operative therapy, first- and second-line management for progressive stages, alongside current gastric cancer treatment guidelines in China. Notably, immunotherapy accounted for 16.17% and 23.28% of first- and second-line treatments for late-stage gastric cancers, and 14.56% and 5.00% for neoadjuvant and adjuvant therapies, respectively. Analysis of survival rates revealed that the 1-, 2-, 3-, 4-, and 5-year survival rates were 74.07%, 54.89%, 44.21%, 37.97%, and 33.53%, respectively. The 5-year survival rates across stages I-IV were 85.07%, 49.34%, 35.56%, and 13.15%, respectively. These findings offer critical insights into the current state of gastric cancer treatment in China and can inform future initiatives to improve therapeutic outcomes for patients with gastric cancer.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"26 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The R-RAS2 GTPase is a signaling hub in triple-negative breast cancer cell metabolism and metastatic behavior","authors":"Claudia Cifuentes, Lydia Horndler, Pilar Grosso, Clara L Oeste, Alejandro M. Hortal, Jennifer Castillo, Isabel Fernández-Pisonero, Alberto Paradela, Xosé Bustelo, Balbino Alarcón","doi":"10.1186/s13045-025-01693-3","DOIUrl":"https://doi.org/10.1186/s13045-025-01693-3","url":null,"abstract":"Recent research from our group has shown that the overexpression of the wild-type RAS-family GTPase RRAS2 drives the onset of triple-negative breast cancer (TNBC) in mice following one or more pregnancies. This phenomenon mirrors human TNBC, where RRAS2 is overexpressed in approximately 75% of cases, particularly in tumors associated with the postpartum period. These findings underscore the relevance of R-RAS2 in TNBC development and progression. We conducted RNA sequencing on tumors derived from conditional knock-in mice overexpressing human wild-type RRAS2 to identify the somatic mutation landscape associated with TNBC development in these mice. Additionally, we developed a TNBC cell line from RRAS2-overexpressing mice, enabling loss-of-function studies to investigate the role of R-RAS2 in various pathobiological parameters of TNBC cells, including cell migration, invasiveness, metabolic activity, and metastatic spread. Furthermore, proteomic analysis of a freshly isolated tumor identified plasma membrane receptors interacting with R-RAS2. Our findings demonstrate that TNBC driven by RRAS2 overexpression exhibits a pattern of somatic mutations similar to those observed in human breast cancer, particularly in genes involved in stemness, extracellular matrix interactions, and actin cytoskeleton regulation. Proteomic analysis revealed that wild-type R-RAS2 interacts with 245 membrane-associated proteins, including key solute carriers involved in cell metabolism (CD98/LAT1, GLUT1, and basigin), adhesion and matrix interaction proteins (CD44, EpCAM, MCAM, ICAM1, integrin-α6, and integrin-β1), and stem cell markers (β1-catenin, α1-catenin, PTK7, and CD44). We show that R-RAS2 regulates CD98/LAT1 transporter-mediated mTOR pathway activation and mediates CD44-dependent cancer cell migration and invasion, thus providing a mechanism by which R-RAS2 promotes breast cancer cell metastasis. R-RAS2 associates with CD44, CD98/LAT1, and other plasma membrane receptors to regulate metabolic activity, actin cytoskeleton reorganization, cell migration, invasion, and distant metastasis formation in TNBC. These findings establish R-RAS2 as a central driver of TNBC malignancy and highlight its potential as a promising therapeutic target, particularly in aggressive, postpartum-associated breast cancers.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"250 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}