Epstein-Barr virus orchestrates spatial reorganization and immunomodulation in the classic Hodgkin lymphoma tumor microenvironment

作者：Yao Yu Yeo, Huaying Qiu, Yunhao Bai, Bokai Zhu, Yuzhou Chang, Fabio Iannelli, Stephanie Pei Tung Yiu, Jason Yeung, Hendrik A. Michel, Yuchen Wang, Yang Wang, Wenrui Wu, K A Wright, Mohammed Shaban, Sam Sadigh, Dingani Nkosi, Vignesh Shanmugam, Philip Rock, Precious Cramer, Julia Paczkowska, Pierre Stéphan, Guanrui Liao, An Huang, Hongbo Wang, Han Chen, Leonie Frauenfeld, Louisa Kaufmann, Stefano Pileri, Bidisha Mitra, Benjamin E. Gewurz, Bing Zhao, Garry P. Nolan, Baochun Zhang, Alex K. Shalek, Michael Angelo, Christian M. Schürch, Faisal Mahmood, Roberto Chiarle, Qin Ma, W. Richard Burack, M A Shipp, Scott J. Rodig, S. Brian Jiang · 发表于：Cell Reports Medicine · 年份：2026 · DOI：10.1016/j.xcrm.2026.102722 · 研究领域：Lymphoma Diagnosis and Treatment、Viral-associated cancers and disorders、Cancer Immunotherapy and Biomarkers

Classic Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells within a T-cell-rich tumor microenvironment (TME). Epstein-Barr virus (EBV) is present in ∼25% of cases, but its contribution to pathogenesis and immunomodulation remains unclear due to technical barriers. Using complementary spatial proteomics and transcriptomics across multi-institutional cohorts, we systematically map key EBV-linked TME reorganization. EBV-positive cHL exhibits distinct immunological features, including memory CD8 T cell enrichment, heightened T cell dysfunction spatially correlated with HRS proximity, and terminally exhausted T cell signatures contrasting with progenitor-exhausted patterns in EBV-negative disease. We identify EBV-encoded LMP1 as a factor in T cell dysfunction through enhanced HRS:CD8 interactions, and its expression level correlates with T cell terminal exhaustion in a distance-dependent manner. This spatial framework dissects viral-mediated immune evasion in the cHL TME, highlighting potential therapeutic opportunities to target virus-associated T cell dysfunction for precision immunotherapy in virus-associated malignancies.