Post-translational regulation of PD-1 protein homeostasis: the ubiquitination-centered crosstalk network

Persistent overexpression of programmed cell death protein 1 (PD-1) on tumor-infiltrating T cells is a key molecular basis for T-cell exhaustion and for the limited efficacy of immune checkpoint blockade. Recent studies have shown that PD-1 is not regulated solely at the transcriptional level. Rather, PD-1 protein abundance is controlled by a multilayered post-translational network in which ubiquitination functions as a central decision point rather than a uniform degradation signal. K48-linked chains generally promote proteasomal turnover, whereas deubiquitination, K63-linked ubiquitination, UFMylation, glycan maturation, and selected trafficking programs can stabilize specific PD-1 pools. Distinct from previous broad surveys of PD-1/PD-L1 post-translational regulation, this review organizes the available evidence along the PD-1 protein life cycle—newly synthesized and incompletely glycosylated precursor, mature plasma-membrane receptor, internalized/recycling receptor, lysosome-directed receptor, nuclear PD-1, and tumor-intrinsic PD-1. We explicitly distinguish mechanisms supported by site-directed, chain-specific, biochemical, or genetic evidence from cellular associations and unresolved models. We also integrate the F-box protein 38 (FBXO38) controversy, phosphorylation-dependent FBW7 and USP5 pathways, NGLY1–MDM2-coupled deglycosylation, UFL1-mediated UFMylation, and membrane trafficking and summarize the evidence and translational limitations in two tables and an integrated schematic. This evidence-graded framework highlights both therapeutic opportunities and the specificity, toxicity, cell-type, and biomarker challenges that must be resolved before PD-1 homeostasis can be targeted clinically.