Wu Tong, Yang Yi, Zong Yuan, Zhao Jiawen, Zhao Xiaoyu, Li Lei, Gao Yiming, Li Ning, Jiang Liting, Xie Yinyin
Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200025, People's Republic of China.
Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
J Transl Med. 2025 Sep 24;23(1):1003. doi: 10.1186/s12967-025-06951-z.
Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous and aggressive hematologic malignancy, with the activated B-cell-like (ABC) subtype displaying particularly poor prognosis due to inherent treatment resistance and elevated recurrence rates. Despite advances in targeted therapies and immunotherapies, a significant proportion of patients experience relapse or refractory disease, highlighting the urgent need for novel biomarkers and innovative therapeutic strategies to improve clinical outcomes.
A multi-dimensional analysis of SH3BP5 expression was performed across DLBCL subtypes, integrating transcriptomic, proteomic, and clinical datasets to assess its correlation with immune infiltration, tumor metabolism, and patient prognosis. Single-cell RNA sequencing data were employed to examine the tumor microenvironment (TME) with higher resolution. Further analysis of the association between SH3BP5 and immune checkpoint gene expression was conducted to explore its potential role in immunotherapy response. Functional in vitro assays were carried out to assess the impact of SH3BP5 knockdown on DLBCL cell proliferation and apoptosis.
The analysis revealed that SH3BP5 is preferentially overexpressed in the ABC subtype of DLBCL across multiple datasets and validated cohorts, and its high expression is significantly associated with poor overall survival. Single-cell transcriptomic profiling demonstrated that SH3BP5 is mainly expressed in malignant B cells and inversely correlated with immune cell infiltration, particularly CD8 + T cells. Mechanistically, pathway enrichment and metabolic assays indicated that SH3BP5 is linked to mitochondrial metabolic reprogramming, promoting oxidative phosphorylation (OXPHOS) and potentially contributing to reduced responsiveness to immune checkpoint inhibitors (ICIs). Functional studies showed that SH3BP5 knockdown significantly suppressed DLBCL cell proliferation, induced apoptosis, and reduced tumor cell viability in vitro.
This study suggests that SH3BP5 may serve as a prognostic biomarker and a potential therapeutic target in DLBCL, particularly within the ABC subtype. By delineating its associations with immune evasion and metabolic reprogramming, these findings provide a mechanistic basis for further exploration of SH3BP5-targeted interventions to help overcome therapy resistance. Future studies in larger clinical cohorts and functional models are warranted to validate these results and assess the potential of integrating SH3BP5 expression profiling into precision medicine strategies for DLBCL.
The study was registered in the Chinese Clinical Trial Registry (ChiCTR2200060430; http://www.chictr.org.cn/ ) on June 1, 2022.
弥漫性大B细胞淋巴瘤（DLBCL）是一种高度异质性和侵袭性的血液系统恶性肿瘤，其中活化B细胞样（ABC）亚型由于固有的治疗耐药性和高复发率，预后特别差。尽管靶向治疗和免疫治疗取得了进展，但仍有相当一部分患者出现复发或难治性疾病，这凸显了迫切需要新的生物标志物和创新治疗策略来改善临床结局。
对DLBCL各亚型进行SH3BP5表达的多维度分析，整合转录组学、蛋白质组学和临床数据集，以评估其与免疫浸润、肿瘤代谢和患者预后的相关性。采用单细胞RNA测序数据以更高分辨率检测肿瘤微环境（TME）。进一步分析SH3BP5与免疫检查点基因表达之间的关联，以探索其在免疫治疗反应中的潜在作用。进行体外功能试验，以评估敲低SH3BP5对DLBCL细胞增殖和凋亡的影响。
分析显示，在多个数据集和验证队列中，SH3BP5在DLBCL的ABC亚型中优先过表达，其高表达与总体生存率差显著相关。单细胞转录组分析表明，SH3BP5主要在恶性B细胞中表达，与免疫细胞浸润，尤其是CD8+T细胞浸润呈负相关。机制上，通路富集和代谢试验表明，SH3BP5与线粒体代谢重编程有关，促进氧化磷酸化（OXPHOS），并可能导致对免疫检查点抑制剂（ICI）的反应性降低。功能研究表明，敲低SH3BP5可显著抑制DLBCL细胞增殖，诱导凋亡，并降低体外肿瘤细胞活力。
本研究表明，SH3BP5可能作为DLBCL，尤其是ABC亚型中的一种预后生物标志物和潜在治疗靶点。通过阐明其与免疫逃逸和代谢重编程的关联，这些发现为进一步探索以SH3BP5为靶点的干预措施提供了机制基础，以帮助克服治疗耐药性。未来有必要在更大的临床队列和功能模型中进行研究，以验证这些结果，并评估将SH3BP5表达谱纳入DLBCL精准医学策略的潜力。
该研究于2022年6月1日在中国临床试验注册中心（ChiCTR2200060430；http://www.chictr.org.cn/ ）注册。
