Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti–Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line–derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor–expressing T cells based on the novel anti-uPAR effectively kill DGC patient–derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.

The mechanistic understanding of virus infection and inflammation in many diseases is incomplete. Normally, messenger RNA (mRNA) tails of replication‐dependent histones (RDH) that safeguard naked nuclear DNAs are protected by a specialized stem‐loop instead of polyadenylation. Here, we showed that infection by various RNA viruses (including severe acute respiratory syndrome coronavirus 2) induced aberrant polyadenylation of RDH mRNAs (pARDH) that resulted in inflammation or cellular senescence, based on which we constructed a pARDH inflammation score (pARIS). We further investigated pARIS elevation in various disease conditions, including different types of virus infection, cancer, and cellular senescence. Notably, we found that pARIS was positively correlated with coronavirus disease 2019 severity in specific immune cell types. We also detected a subset of HIV‐1 elite controllers characterized by pARDH “flipping” potentially mediated by HuR. Importantly, pARIS was positively associated with transcription of endogenous retrovirus but negatively associated with most immune cell infiltration in tumors of various cancer types. Finally, we identified and experimentally verified two pARIS regulators, ADAR1 and ZKSCAN1, which was first linked to inflammation. The ZKSCAN1 was known as a transcription factor but instead was shown to regulate pARIS as a novel RNA binding protein. Both regulators were upregulated under most infection and inflammation conditions. In conclusion, we unraveled a potential antiviral mechanism underlying various types of virus infections and cancers.