Work

Post-Translational Control of PD-L1 in Cancer Immunity and Immunotherapy Resistance

Year: 2026

Type: review

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.

Source: ImmunoTargets and Therapy

DOI: 10.2147/itt.s637720

Authors: Miaomiao Li, Jiahui Li, Wentong Tian, Jiachang Tao, Ziyi Fu, Yaoxin Gao