Regulation of PD-L1 glycosylation and advances in cancer immunotherapy

Protein glycosylation plays a versatile role in regulating homeostasis, such as cell migration, protein sorting, and the immune response. Drugs aimed at targeting glycosylation have strong implications for immunity enhancement, diagnosis, and cancer regression. Programmed death-ligand 1 (PD-L1), expressed in cancer or antigen-presenting cells, binds to programmed cell death protein 1 (PD-1) and suppresses T cells. Glycosylation of PD-L1 at N35, N192, N200, and N219 stabilizes PD-L1 on the cancer cell surface, which contributes to immune evasion by inhibiting T cell activity. To date, at least six glycosyltransferases and four associate proteins are known to regulate PD-L1 glycosylation. Terminal modifications such as poly-N-acetyl-lactosamine (poly-LacNAC), sulfation, and sialylation are commonly found on PD-L1, acting as an immune recognition ligand and regulating certain immune responses. Studies have identified many mechanisms and potential therapeutic targets within the glycosylation pathways of PD-L1, revealing their involvement in cancer pathology, immune evasion, and resistance to immunotherapy. In this review, we covered the glycoforms, terminal moiety, binding lectin, glycosyltransferase, as well as sugar analogs focusing on glycosylated PD-L1. We present a mechanism that originates from the endoplasmic reticulum (ER)-Golgi apparatus (Golgi) and its subsequent translocation to the cell membrane. This pathway determines the immune suppression function of PD-L1 and therefore regulates the immune response such as T cells, monocytes, and macrophages. This collection of findings underscores the significance of glycosylation in the role of PD-L1 in cancer and highlights multiple potential targets and strategies for improving therapeutic intervention and diagnostic techniques.