结外自然杀伤/T 细胞淋巴瘤 (ENKTL) 在放化疗后复发率很高。耐药性可以通过小细胞外囊泡 (sEV) 的负载介导。在这里，我们发现肿瘤细胞和血清 sEV 中高丰度的跨膜糖蛋白 CD98hc 与 ENKTL 进展和耐药性相关。从机制上讲，聚乙二醇化天冬酰胺酶 (PEG-asp) 治疗（一种针对 ENKTL 的常见疗法）促进转录因子 ATF4 易位至细胞核，在细胞核中它被 USP1 稳定，随后增加 CD98hc 表达。在肿瘤细胞衍生的 sEV 中递送的 CD98hc 增加了培养的人 NK 淋巴瘤细胞系、动物模型和难治性/复发性 ENKTL 患者样本中的肿瘤细胞增殖和耐药性。此外，抑制USP1和EV分泌可协同增强PEG-asp的细胞毒性。这些数据表明，靶向 CD98hc 治疗 ENKTL 可能有利于克服耐药性。

Extranodal natural killer/T cell lymphoma (ENKTL) shows a high rate of recurrence after chemoradiotherapy. Drug resistance can be mediated by the cargo of small extracellular vesicles (sEVs). Here, we show that high abundance of the transmembrane glycoprotein CD98hc in tumor cells and serum sEVs was associated with ENKTL progression and drug resistance. Mechanistically, PEGylated-asparaginase (PEG-asp) treatment, a common therapy against ENKTL, promoted the translocation of the transcription factor ATF4 to the nucleus, where it was stabilized by USP1 and subsequently increased CD98hc expression. CD98hc delivered in tumor cell-derived sEVs increased tumor cell proliferation and drug resistance in a cultured human NK lymphoma cell line, animal models, and samples from patients with refractory/relapse ENKTL. Moreover, inhibiting both USP1 and EV secretion synergistically enhanced the cytotoxicity of PEG-asp. These data suggest that targeting CD98hc in the treatment of ENKTL may be beneficial in overcoming drug resistance.