Post-Translational Control of PD-L1 in Cancer Immunity and Immunotherapy Resistance
5 affiliations
- 1Department of Epidemiology and Biostatistics, School of Public Health, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
- 2Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
- 3Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
- 4Department of Radiation Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
- 5Cell Research and Transformation Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
Abstract
Programmed death-ligand 1 (PD-L1) is classically defined as a tumor cell surface ligand that suppresses T cell immunity by binding to programmed death protein 1 (PD-1). Though this model still exists today, it does not capture the entirety of PD-L1 biology. In addition to transcriptional induction, PD-L1 is largely controlled through several post-translational modifications (PTMs). Phosphorylation, glycosylation, ubiquitination, deubiquitination, acetylation, S-palmitoylation, as well as recently described modifications, all modulate PD-L1 stability, cell membrane residence, intracellular trafficking, nuclear localization, secretion and potential drug targeting. PTMs of PD-L1 do not occur only through independent events. These events form an interconnected state space for PD-L1. PD-L1 states determine PD-L1 retention at the membrane, degradation, nuclear localization, and extracellular secretion via extracellular vesicles. Building on prior PTM-centered reviews, this review advances a PD-L1 functional-state framework linking PTM crosstalk to membrane, nuclear, and extracellular-vesicle/exosomal PD-L1 pools, resistance phenotypes, and a PTM-focused, AI-assisted multimodal biomarker roadmap for translational stratification. We further discuss how PTM-targeted assays and multimodal analysis methods can contribute to optimizing immunotherapy indications and guiding rational combination strategies.
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BibTeX
@article{li2026posttranslational,
title = {{Post-Translational Control of PD-L1 in Cancer Immunity and Immunotherapy Resistance}},
author = {Miaomiao Li and Jiahui Li and Wentong Tian and Jiachang Tao and Ziyi Fu and Yaoxin Gao},
journal = {ImmunoTargets and Therapy},
year = {2026},
month = oct,
doi = {10.2147/itt.s637720},
url = {https://doi.org/10.2147/itt.s637720},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Post-Translational Control of PD-L1 in Cancer Immunity and Immunotherapy Resistance
AU - Miaomiao Li
AU - Jiahui Li
AU - Wentong Tian
AU - Jiachang Tao
AU - Ziyi Fu
AU - Yaoxin Gao
PY - 2026
DA - 2026/10/30
JO - ImmunoTargets and Therapy
DO - 10.2147/itt.s637720
UR - https://doi.org/10.2147/itt.s637720
AB - Programmed death-ligand 1 (PD-L1) is classically defined as a tumor cell surface ligand that suppresses T cell immunity by binding to programmed death protein 1 (PD-1). Though this model still exists today, it does not capture the entirety of PD-L1 biology. In addition to transcriptional induction, PD-L1 is largely controlled through several post-translational modifications (PTMs). Phosphorylation, glycosylation, ubiquitination, deubiquitination, acetylation, S-palmitoylation, as well as recently described modifications, all modulate PD-L1 stability, cell membrane residence, intracellular trafficking, nuclear localization, secretion and potential drug targeting. PTMs of PD-L1 do not occur only through independent events. These events form an interconnected state space for PD-L1. PD-L1 states determine PD-L1 retention at the membrane, degradation, nuclear localization, and extracellular secretion via extracellular vesicles. Building on prior PTM-centered reviews, this review advances a PD-L1 functional-state framework linking PTM crosstalk to membrane, nuclear, and extracellular-vesicle/exosomal PD-L1 pools, resistance phenotypes, and a PTM-focused, AI-assisted multimodal biomarker roadmap for translational stratification. We further discuss how PTM-targeted assays and multimodal analysis methods can contribute to optimizing immunotherapy indications and guiding rational combination strategies.
SN - 2253-1556
ER -