2026/06/20 by Y Zhang, Xueyan Zhou, Y Y Wei +22 · 1 voice
Immunology and Microbiology · Medicine · #Immune Cell Function and Interaction #Cancer Immunotherapy and Biomarkers #Pancreatic and Hepatic Oncology Research
paper · doi:10.1016/j.celrep.2026.117583
openalex publication_date 2026/06/20 · openalex created_date 2026/06/20 · openalex updated_date 2026/07/31
Immune checkpoint blockade (ICB) shows limited efficacy in pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrate that ICB-induced IFN-γ signaling upregulates H2-T23 on pancreatic tumor cells, which interacts with NKG2A on NK cells to induce NK cell senescence through activation of p38 MAPK and STAT1/3 pathways. This impairs NK cell cytotoxicity and restricts antitumor immunity. Dual blockade of PD-1 and NKG2A effectively prevents NK cell senescence, restores NK cell function, and enhances antitumor immunity. Mechanistically, the combination therapy promotes NK cell-derived CCL5 and facilitates CD8 + T cell recruitment in an NK cell-dependent manner, thereby activating both innate and adaptive immunity. Analysis of single-cell sequencing data across nine cancer types further revealed increased NK cell senescence after immunotherapy, suggesting a potentially common pan-cancer mechanism. These findings identify NK cell senescence as a key mechanism underlying immunotherapy resistance and support dual targeting of PD-1 and NKG2A as a promising therapeutic strategy for PDAC.