Diffuse large B-cell lymphoma cell-derived exosomal NSUN2 stabilizes PDL1 to promote tumor immune escape and M2 macrophage polarization in a YBX1-dependent manner

Huayu Ling; Yuling Li; Panjun Wang; Zhengxiang Zhang; Zhong Yang

doi:10.1016/j.abb.2025.110322

Diffuse large B-cell lymphoma cell-derived exosomal NSUN2 stabilizes PDL1 to promote tumor immune escape and M2 macrophage polarization in a YBX1-dependent manner

Arch Biochem Biophys. 2025 Jan 24:110322. doi: 10.1016/j.abb.2025.110322. Online ahead of print.

Authors

Huayu Ling¹, Yuling Li¹, Panjun Wang², Zhengxiang Zhang¹, Zhong Yang³

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu City, Anhui Province, 241000, China.
² Department of Hematology, The Second Affiliated Hospital of Suzhou University, Suzhou City, Jiangsu Province, 215008, China.
³ Department of Nuclear Medicine, Hefei BOE Hospital, Hefei City, Anhui Province, 241000, China. Electronic address: Yangzhong2012@126.com.

PMID: 39864779
DOI: 10.1016/j.abb.2025.110322

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive form of non-Hodgkin's lymphoma with a complex etiology. NOP2/Sun domain 2 (NSUN2) is an RNA methyltransferase that has been linked to the regulation of gene expression in various cancers. However, the function of NSUN2 in DLBCL, specifically its contribution to exosome-driven tumor progression, remains to be thoroughly elucidated.

Methods: Quantitative real-time polymerase chain reaction was used to analyze the expression of NSUN2 and programmed death ligand 1 variant (PDL1). Western blotting assay was performed to detect the protein levels of NSUN2, PDL1 and Y-box binding protein 1 (YBX1). Cell proliferation was analyzed by cell counting kit-8 and 5-Ethynyl-2'-deoxyuridine assays. Cell apoptosis and CD206-positive cells were quantified by flow cytometry. The levels of tumor necrosis factor-alpha and interferon-γ in cell supernatant were analyzed by enzyme-linked immunosorbent assays. m6A RNA immunoprecipitation and RNA pull-down assays were performed to determine the association between NSUN2 and PDL1. An RNA immunoprecipitation assay was used to analyze the association of YBX1 and PDL1. In vitro findings were validated in a mouse model.

Results: NSUN2 was overexpressed in DLBCL tissues and cells. DLBCL cell-derived exosomes facilitated the transfer of NSUN2 to DLBCL cells, which in turn promoted tumor cell proliferation, M2 macrophage polarization, and immune escape and inhibited cell apoptosis. In addition, NSUN2 stabilized PDL1 mRNA through an m5C-dependent mechanism and a YBX1-dependent pathway. Moreover, the suppression of PDL1 significantly mitigated the effects induced by NSUN2 within DLBCL cell-derived exosomes on cellular proliferation, apoptosis, M2 macrophage polarization, and immune evasion. Further, DLBCL cell-derived exosomal NSUN2 promoted tumor growth by regulating PDL1.

Conclusion: NSUN2 in DLBCL cell-derived exosomes stabilized PDL1 in a YBX1-dependent manner and thus promoted tumor immune escape and M2 macrophage polarization. These findings highlight the potential of targeting the NSUN2-PDL1 axis as a novel therapeutic strategy for DLBCL.

Keywords: Diffuse large B-cell lymphoma; NSUN2; PDL1; YBX1; exosomes.