Posttranslational regulatory mechanism of PD-L1 in cancers and associated opportunities for novel small-molecule therapeutics

Abstract

Despite the tremendous progress in cancer research over the past few decades, effective therapeutic strategies are still urgently needed. Accumulating evidence suggests that immune checkpoints are the cause of tumor immune escape. PD-1/PD-L1 are among them. Posttranslational modification is the most critical step for protein function, and the regulation of PD-L1 by small molecules through posttranslational modification is highly valuable. In this review, we discuss the mechanisms of tumor cell immune escape and several posttranslational modifications associated with PD-L1 and describe examples in which small molecules can regulate PD-L1 through posttranslational modifications. Herein, we propose that the use of small molecule compounds that act by inhibiting PD-L1 through posttranslational modifications is a promising therapeutic approach with the potential to improve clinical outcomes for cancer patients.

Keywords: PD-L1; cancer; posttranslational modification; small molecule compound.

Figure 1

Mechanisms of immunotherapy Tumor cells inhibit the killing of tumors by immune cells through the upregulation of immune checkpoint molecular receptors, thus achieving immune escape. The classical immune checkpoints and their receptors are PD-1 and CTLA-4. The use of immune checkpoint inhibitors can prevent the binding of immune checkpoints to immune receptors and thus activate T cells to exert antitumor effects.

Figure 2

Posttranslational modifications of PD-L1 in tumor cells The intracellular PD-L1 protein is subjected to several forms of posttranslational modifications before membrane uploading, among which phosphorylation and polyubiquitination promote the degradation of PD-L1, whereas glycosylation, palmitoylation, acetylation, and deubiquitination can improve the stability of the PD-L1 protein to make it function normally on the membrane.

Figure 3

The search for new immune checkpoint inhibitors is promising Although CTLA-4 and PD-1/PD-L1 inhibitors have demonstrated significant efficacy, they have low response rates in most patients and are expensive; therefore, the development of new ICIs for cancer treatment is currently a major research interest.