Early dynamics of a neutrophil interferon program drive immunotherapy resistance and limit durable anti-tumor immunity
Year: 2026
Type: preprint
Abstract: Despite the remarkable success of immune checkpoint blockade (ICB), durable clinical benefit remains limited to a subset of patients, highlighting the need for predictive biomarkers and new therapeutic targets. Here, we investigated the early immune dynamics associated with anti-PD1 responsiveness using longitudinal single-cell transcriptomics, spatial transcriptomics, and neutrophil-specific genetic perturbations in preclinical models of triple-negative breast cancer. We identified a conserved neutrophil interferon-stimulated gene (ISG) program that emerges before overt tumor divergence and predicts resistance to anti-PD1 therapy. Successful treatment was associated with an early reduction of IFN-responsive neutrophils in both blood and tumor tissues, whereas persistent neutrophil IFN signaling correlated with therapeutic resistance. Mechanistically, genetic disruption of either type I or type II interferon signaling in neutrophils enhanced anti-PD1 efficacy and promoted durable anti-tumor immune memory. Spatial analyses further revealed an inverse association between IFN-responsive neutrophils and tertiary lymphoid structure-enriched regions during effective therapy. Together, these findings identify IFN-responsive neutrophils as early determinants of immunotherapy outcome and establish dynamic neutrophil interferon programs as candidate blood-based biomarkers and therapeutic targets for cancer immunotherapy.
Authors: Yang Gao, Emmanuel Anning, Linhua Wang, Yating Cheng, Ling Wu, Jun Wang, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Jun Liu, Liqun Yu, Yunfeng Ding, Weijie Zhang, David G. Edwards, Yi-Hsuan Wu, Hilda L. Chan, Dane Hoffman, Siyue Wang, Tobie D. Lee, Luis B. Dominguez, Noa Peled, Xuan Li, Xiang Chen, Charlotte H. Rivas, Na Zhao, Sebastian J. Calderon, Diego A. Pedroza, Alex J. Smith, Nan Guan, Zhandong Liu, Jeffrey M. Rosen, Xiang H.-F. Zhang
Institutions: Baylor College of Medicine, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Texas Children's Hospital, Houston Methodist, Memorial Sloan Kettering Cancer Center, Chinese Academy of Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hydrobiology, Second Affiliated Hospital of Zhejiang University, Zhejiang University, Dan L Duncan Comprehensive Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1127673601, Comprehensive Cancer Epigenomics Core Facility, G1298056475, G1504377518, G2227931368, Mechanistic and therapeutic investigation of secondary metastatic seeding from breast cancer bone lesion, Translational Research in Breast Cancer, G2850151910, G2859315832, G3102002109, G4065300843, G5465708471, Rewired Metabolism Regulates Vessel Normalization and Immunosuppression, G5852908003, G7022586960, G7514240623, Advanced Multiparameter Cytometry and Cell Sorting Core, G7837447426, Osteoclast-Independent Mechanisms of Early-Stage Bone Colonization of Breast Cancer, G8153776008, G8216758759, G8355490421, Osteogenic Niche Biology in Progression and Endocrine Resistance of Bone Metastases, G9000240210, G949969490
OpenAlex ID: W7215125432