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Immune checkpoint blockade has demonstrated success in treating cancer but can lead to immune-related adverse events (irAEs), illustrating the centrality of these pathways in tolerance. Here, we describe programmed cell death protein 1 (PD-1) control of T cell responses, focusing on its unique restraint of regulatory T cell function. We examine successes and limitations of checkpoint blockade immunotherapy and review clinical and mechanistic features of irAEs. Last, we discuss strategies to modulate PD-1 blockade to enhance antitumor immunity while limiting autoimmunity.
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http://dx.doi.org/10.1126/sciimmunol.abf4034 | DOI Listing |
J Clin Invest
September 2025
State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Pancreatic cancer (PC) is notoriously resistant to both chemotherapy and immunotherapy, presenting a major therapeutic challenge. Epigenetic modifications play a critical role in PC progression, yet their contribution to chemoimmunotherapy resistance remains poorly understood. Here, we identified the transcription factor ZEB1 as a critical driver of chemoimmunotherapy resistance in PC.
View Article and Find Full Text PDFNucleic Acids Res
September 2025
Department of Thoracic Surgery, West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu 610041, China.
T-cell receptor (TCR) repertoire sequencing allows researchers to analyze millions of TCRs, providing unparalleled precision in understanding immune responses and enabling broad applications. However, existing TCR-related databases are based on a limited number of samples. Here, we present TCRdb2.
View Article and Find Full Text PDFPLoS Pathog
September 2025
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
Zika virus (ZIKV) has emerged as a rising concern in global health in recent years. The role of PD-1/PD-L1 immune checkpoint in acute ZIKV infection remains to be understood. In this study we demonstrated the activation of PD-1/PD-L1 immune checkpoint by ZIKV.
View Article and Find Full Text PDFCancer Immunol Res
September 2025
University of Pennsylvania, Philadelphia, PA, United States.
Pancreatic ductal adenocarcinoma (PDA) is defined by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., PD-1 and CTLA-4).
View Article and Find Full Text PDFOncol Res
September 2025
Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, largely driven by an immunosuppressive tumor microenvironment (TME) that facilitates tumor growth, immune escape, and resistance to therapy. Although immunotherapy-particularly immune checkpoint inhibitors (ICIs)-has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses, their clinical benefit as monotherapy remains suboptimal. This limitation is primarily attributed to immunosuppressive components within the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs).
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