弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的淋巴恶性肿瘤，表现出巨大的遗传和转录组异质性。目前的治疗指南建议采用以蒽环类为主的一线化学免疫疗法，其治愈率约为 65%。然而，剩下的患者将面临复发或难治性疾病，即使在CAR-T细胞时代，这些疾病也很难治疗。在本期《癌症研究》中，Marullo 及其同事研究了新批准的 XPO1 抑制剂 selinexor 在淋巴瘤治疗中的肿瘤抑制活性的生物学基础。在涵盖基因组和生化方法的转化工作中，结合体内验证实验和 I 期临床试验，他们证明，在 DNA 损伤时，XPO1 通过 RNA 结合蛋白 THOC4 和 eIF4E 选择性输出编码参与基因组维护的蛋白质的转录本。这种输出过程的药理学拦截增强了各种淋巴瘤模型中的化疗敏感性，并且联合selinexor加化学免疫疗法在患者中显示出良好的毒性特征和疗效的早期证据。

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and displays vast genetic and transcriptomic heterogeneity. Current treatment guidelines recommend frontline chemoimmunotherapy consisting of an anthracycline backbone, which produces cure rates of ~65%. However, the remaining patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. In this issue of Cancer Research, Marullo and colleagues investigate the biological underpinnings of the tumor suppressive activity of the newly approved XPO1 inhibitor selinexor in the treatment of lymphoma. In a translational effort covering genomic and biochemical approaches, combined with in vivo validation experiments and a phase I clinical trial, they demonstrate that upon DNA damage, XPO1 selectively exports transcripts encoding proteins involved in genome maintenance via the RNA-binding proteins THOC4 and eIF4E. Pharmacologic interception of this export process enhances chemosensitivity in various lymphoma models, and combined selinexor plus chemoimmunotherapy displays a favorable toxicity profile and early evidence of efficacy in patients.