Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6–activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum–associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti–T cell immunoglobulin mucin-3 (anti–Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti–IL-6 and anti–Tim-3 as an effective marker-guided therapeutic strategy.

Rationale: Messenger RNA (mRNA) vaccine outperforms other kinds of cancer immunotherapy due to its high response rates, easy preparation, and wide applicability, which is considered as one of the most promising forms of next-generation cancer therapies. However, the inherent instability and insufficient protein expression duration of mRNA limit the efficacy and widespread application of the vaccine.

Unlike hematological malignancies, solid tumors have proved to be less susceptible to chimeric antigen receptor (CAR)‐T cell therapy, which is partially caused by reduced accumulation of therapeutic T cells in tumor site. Since efficient trafficking is the precondition and pivotal step for infused CAR‐T cells to exhibit their anti‐tumor function, strategies are highly needed to improve the trafficking ability of CAR‐T cells for solid tumor treatment. Here, based on natural lymphocyte chemotaxis theory and characteristics of solid tumor microenvironments, we explored the possibility of enhancing CAR‐T cell trafficking by using chemokine receptors. Our study found that compared with other chemokines, several CXCR2 ligands showed relatively high expression level in human hepatocellular carcinoma tumor tissues and cell lines. However, both human peripheral T cells and hepatocellular carcinoma tumor infiltrating T cells lacked expression of CXCR2. CXCR2‐expressing CAR‐T cells exhibited identical cytotoxicity but displayed significantly increased migration ability in vitro. In a xenograft tumor model, we found that expressing CXCR2 in CAR‐T cells could significantly accelerate in vivo trafficking and tumor‐specific accumulation, and improve anti‐tumor effect of these cells.