DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps PMID: 40816293

ADC Targets in Oncology

2026-04-10

DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps

Cancer Cell. 2025 Sep 8;43(9):1758-1775.e8. doi: 10.1016/j.ccell.2025.07.014.

Degao Chen ¹ , Zheng Jin ² , Han Chu ³ , Yucui Wu ¹ , Yangping Bian ¹ , Ting Yuan ¹ , Hao Lv ¹ , Qiuyu Xia ⁴ , Lei Wang ⁵ , Qian Chu ⁵ , Quanxing Liu ⁶ , Dong Zhou ⁶ , Wenfeng Fang ⁷ , Xiaoming Cheng ⁸ , Haoran Zha ⁹ , Haixia Long ¹ , Li Zhang ⁷ , Jigang Dai ⁶ , Yisong Y Wan ¹⁰ , Qi-Jing Li ¹¹ , Qingzhu Jia ¹² , Xindong Liu ¹³ , Bo Zhu ¹⁴

Affiliations

1. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China.
2. Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing 400016, China.
3. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, College of Life Sciences, Sichuan University, Chengdu 610064, China.
4. School of Life Sciences, Chongqing University, Chongqing 400044, China.
5. Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
6. Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
7. Medical Oncology Department, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
8. Department of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
9. Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing 100088, China.
10. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
11. Institute of Molecular and Cell Biology (IMCB) and Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138668, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.
12. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China. Electronic address: [email protected].
13. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Jinfeng Laboratory, Chongqing 401329, China. Electronic address: [email protected].
14. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing 400016, China; Jinfeng Laboratory, Chongqing 401329, China. Electronic address: [email protected].

Abstract

CD8⁺ T cell exclusion and dysfunction in the tumor microenvironment (TME) are among the most challenging obstacles for anti-PD-(L)1 therapy. Here, we report that tumor-infiltrating dendritic cell (DC)-specific expression of the deoxyribonuclease, DNASE1L3, is positively correlated with favorable outcomes of anti-PD-(L)1 treatment in Cancer patients. DNASE1L3 conditional knockout in DCs leads to enhanced tumor growth and diminishes anti-PD-L1 therapeutic efficacy by impairing infiltration and effector functions of CD8⁺ T cells. Conversely, injection with DNASE1L3 promotes CD8⁺ T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3⁺ DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8⁺ T cells in tumors, enabling establishment of cytotoxic CD8⁺ T cell hubs in human cancers. Our findings reveal a role of DC in regulating intratumoral CD8⁺ T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.

Keywords

CD8(+) T cell; DNASE1L3; anti-PD-1/PD-L1 therapy; cellular community; dendritic cell; immune hubs; neutrophil extracellular traps.