Abstract：
Tumor cells can express the immune checkpoint protein programmed death-1 (PD-1), but how cancer cell-intrinsic PD-1 is regulated in response to cellular stresses remains largely unknown. Here, we uncover a unique mechanism by which the chemotherapy drug doxorubicin (Dox) regulates cancer cell-intrinsic PD-1. Dox upregulates PD-1 mRNA while reducing PD-1 protein levels in tumor cells. Although Dox shortens the PD-1 half-life, it fails to directly induce PD-1 degradation. Instead, we observe that Dox promotes the interaction between peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1) and PD-1, facilitating NGLY1-mediated PD-1 deglycosylation and destabilization. The maintenance of PD-1 sensitizes tumor cells to Dox-mediated antiproliferative effects. Our study unveils a regulatory mechanism of PD-1 in response to Dox and highlights a potential role of cancer cell-intrinsic PD-1 in Dox-mediated antitumor effects.
摘要：
肿瘤细胞可以表达免疫检查点蛋白程序性死亡-1（PD-1），但是癌细胞固有的PD-1如何响应细胞应激而受到调节仍在很大程度上未知.这里,我们揭示了化疗药物多柔比星(Dox)调节癌细胞固有PD-1的独特机制.Dox上调PD-1mRNA，同时降低肿瘤细胞中的PD-1蛋白水平。虽然Dox缩短了PD-1的半衰期,它不能直接诱导PD-1降解。相反，我们观察到Dox促进肽-N(4)-(N-乙酰-β-葡糖胺基)天冬酰胺酶(NGLY1)和PD-1之间的相互作用,促进NGLY1介导的PD-1去糖基化和去稳定化.PD-1的维持使肿瘤细胞对Dox介导的抗增殖作用敏感。我们的研究揭示了PD-1响应Dox的调节机制，并强调了癌细胞固有PD-1在Dox介导的抗肿瘤作用中的潜在作用。
