Post-Translational Modulation of PD-L1 in Cancer Immunotherapy

Programmed death-ligand 1 (PD-L1) is a transmembrane protein that binds the inhibitory receptor PD-1 on T cells, dampening antitumour immunity. Beyond transcriptional control, PD-L1 undergoes an array of post-translational modifications (PTMs) that regulate its abundance, subcellular localisation and interactions with the immune system. N-linked glycosylation at specific asparagine residues protects PD-L1 from proteasomal degradation, whereas phosphorylation by kinases such as GSK3β can prime it for ubiquitin-mediated turnover. Ubiquitination itself is context-dependent: K48-linked chains direct PD-L1 to the proteasome, while K63-linked modifications may stabilise the protein or promote non-degradative trafficking. SUMOylation and acetylation further fine-tune PD-L1 folding and cell-surface presentation. Recent work has also revealed dynamic redistribution of PD-L1 to organelles such as mitochondria, influencing responses to combination chemo-immunotherapy. Together, these modifications form an integrated regulatory network that modulates immune checkpoint strength, tumour immune evasion and the clinical efficacy of PD-1/PD-L1 blockade. Therapeutic strategies targeting PTM enzymes or pathways—ranging from glycosyltransferase inhibitors to deubiquitinase blockers—offer promising routes to enhance checkpoint inhibitor responses across diverse cancer types.

Research from Nature Portfolio

Glycosylation is pivotal for PD-L1 stability and immune-suppressive function. Foundational studies demonstrated that phosphorylation of PD-L1 by glycogen synthase kinase 3β (GSK3β) triggers its recognition by the E3 ligase β-TrCP, leading to proteasomal degradation. N-linked glycan addition at residues N192, N200 and N219 antagonises this interaction, enhancing PD-L1 half-life on the tumour cell surface and suppressing T-cell activity. Separately, the epithelial–mesenchymal transition (EMT)/β-catenin/STT3 axis was shown to upregulate STT3 glycosyltransferase expression, thereby promoting PD-L1 N-glycosylation, stabilisation and enrichment on cancer stem cells. EMT-induced STT3 not only increases global PD-L1 levels but also contributes to immune evasion in both stem-like and bulk tumour cell populations, highlighting a lineage-specific mechanism for checkpoint regulation and potential for MET-inducing agents to reverse PD-L1 stabilisation.

Post-Translational Modulation of PD-L1 in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in post-translational modulation of pd-l1 in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

N-linked glycosylation: Attachment of oligosaccharide chains to asparagine residues that stabilises PD-L1 and hinders its recognition by degradation machinery.

Ubiquitination: Covalent linkage of ubiquitin to lysine residues; K48-linked chains target proteins for proteasomal destruction, K63-linked chains modulate signalling or trafficking.

SUMOylation: Conjugation of small ubiquitin-like modifiers (SUMOs) that can influence protein–protein interactions, subcellular localisation and stability.

Mitophagy: Selective autophagic removal of mitochondria, here co-opted to degrade PD-L1 upon PINK1 recruitment.

STT3 glycosyltransferase: Catalytic subunit of the oligosaccharyltransferase complex that mediates N-glycan transfer to nascent PD-L1 polypeptides.

References

1. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nature Communications (2016).
2. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nature Communications (2018).
3. TRIM28 promotes the escape of gastric cancer cells from immune surveillance by increasing PD-L1 abundance. Signal Transduction and Targeted Therapy (2023).
4. Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria. Cell Research (2023).
5. PD-L1 degradation pathway and immunotherapy for cancer. Cell Death & Disease (2020).