Dual blockade of PD-1 and NKG2A prevents NK cell senescence and reprograms the immunosuppressive microenvironment in pancreatic cancer PMID: 42322608

ADC Targets in Oncology

2026-04-10

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].

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.