IL-5-producing CD4(+) T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer.

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Abstract

[Indexed for MEDLINE] Conflict of interest statement: Declaration of interests O.S.B., H.G., L.S., L.V., O.I.I., E.v.D., N.B., C.K., M.D., K. Kersten, M.B., D.P., C.-S.H., K.V., E.A.M.R., D.K., L.H., K. Kos, I.S.A., P.K., R.B., and D.S.T. have no competing interests to declare. M.C. reports funding to the institute from BMS and Roche/Genentech and an advisory role for BMS, outside the submitted work. W.S.M.E.T. reports receiving grants from MSD during the conduct of the PEMBRO-RT trial. P.B. reports receiving grants and medication delivery from MSD during the conduct of the PEMBRO-RT trial as well as grants and consultancy fees from BMS outside the submitted work. E.E.V. is legally responsible for all contracts with pharmaceutical companies at the NKI and reports research funding from BMS, outside the submitted work. L.F.A.W. reports funding to the institute from Genmab BV. K.E.d.V. reports research funding from Roche/Genentech and is consultant for Macomics, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche/Genentech, AZ, and an advisory role for BMS, Roche, MSD, and Daiichi Sankyo, outside the submitted work. 12. Oncogene. 2025 Jul;44(26):2186-2200. doi: 10.1038/s41388-025-03375-3. Epub 2025 Apr 12. KPNA2 promotes osteosarcoma progression by regulating the alternative splicing of DDX3X mediated by YBX1. Cao L(#)(1)(2), Jia K(#)(1), Van Tine BA(#)(2), Yu Y(#)(1), Peng Y(1), Chen X(1), Pan Q(1), Yang W(1), Zhang Z(3), Shao Z(4), Wu W(5). Author information: (1)Department of Orthopaedic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. (2)Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (3)Department of Orthopaedic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. zhicaizhang@126.com. (4)Department of Orthopaedic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. szwpro@163.com. (5)Department of Orthopaedic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. waynewu@hust.edu.cn. (#)Contributed equally Osteosarcoma (OS) is a rapidly progressive primary malignant bone tumor that occurs in children and adolescents aged between 15 and 19 years and adults aged over 60 years. As alternative splicing (AS) changes caused by abnormal splicing factors contribute to tumor progression, gene expression and AS analyses were performed on 44 osteosarcoma patients to create a genome-wide co-expression network of RNA-binding proteins (RBPs), AS events, and AS genes. A gain- or loss-of-function osteosarcoma cell model was established, and an interactive network analysis and enrichment analysis were performed. Karyopherin Subunit Alpha 2 (KPNA2) negatively correlated with patient survival. KPNA2 transports splicing factor Y-box Binding Protein 1 (YBX1) into the nucleus and YBX1 accelerates the degradation of the ATP-dependent RNA helicase DDX3X (DDX3X) through the nonsense-mediated decay (NMD) pathway to promote intron retention of the DDX3X gene, thus reducing DDX3X protein levels. KPNA2/YBX1 axis regulates the stability of DDX3X mRNA and cell cycle progression. KPNA2/YBX1/DDX3X axis might be potential targets for inhibiting disease progression and improving OS patient survival. It integrates AS control of DDX3X into the progression of OS and represents a potential prognostic biomarker and therapeutic target for OS therapy. © 2025. The Author(s). DOI: 10.1038/s41388-025-03375-3 PMCID: PMC12183081