Doxorubicin induces deglycosylation of cancer cell‐intrinsic PD‐1 by NGLY1

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.