Dual blockade of PD-1 and NKG2A prevents NK cell senescence and reprograms the immunosuppressive microenvironment in pancreatic cancer

  • Cell Rep. 2026 Jun 20;45(7):117583. doi: 10.1016/j.celrep.2026.117583.
Yu Zhang  1 ,  Xueyan Zhou  2 ,  Yuhao Wei  1 ,  Hao Zhang  3 ,  Yunuo Zhao  1 ,  Huan Tong  1 ,  Zedong Jiang  1 ,  Guangqi Li  4 ,  Yuting Jiang  1 ,  Xiaomeng Yin  1 ,  Shen Li  1 ,  Nan Lin  1 ,  Lusi Feng  1 ,  Haorui Zhou  1 ,  Qianlong Kang  1 ,  Jieping Qiu  1 ,  Jingwen Wei  1 ,  Keqin Tan  1 ,  Xiaoqian Yang  1 ,  Renwei Li  1 ,  Jiaqing Yang  1 ,  Shiyi Tang  1 ,  Shengxin Zhang  1 ,  Jifeng Liu  5 ,  Xuelei Ma  6
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Biotherapy, Cancer Center State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, and Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan, China.
  • 3. Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • 4. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Radiation Oncology, Precision Radiation in Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
  • 5. Department of Otolaryngology-Head and Neck Surgery, Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu, China; State Key Laboratory of Intelligent Construction and Healthy Operation and Maintenance of Deep Underground Engineering, Sichuan University, Chengdu, China. Electronic address: [email protected].
  • 6. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: [email protected].
PMID: 42322608 DOI: 10.1016/j.celrep.2026.117583
Abstract

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.

Keywords
CP: cancer; CP: immunology; Parabrachial nucleus; chemogenetics; chronic pain; optogenetics.
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