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

Yeo YY, Qiu H, Bai Y, Zhu B, Chang Y, Iannelli F, Yiu SPT, Yeung J, Michel HA, Wang Y, Wang Y, Wu W, Wright K, Shaban M, Sadigh S, Nkosi D, Shanmugam V, Rock P, Cramer P, Paczkowska J, Stephan P, Liao G, Huang AY, Wang H, Chen H, Frauenfeld L, Kaufmann L, Pileri S, Mitra B, Gewurz BE, Zhao B, Nolan GP, Zhang B, Shalek AK, Angelo M, Schürch CM, Mahmood F, Chiarle R, Ma Q, Burack WR, Shipp MA, Rodig SJ, Jiang S.

Cell Rep Med, 7, 4, March, 2026

Abstract

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.

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