PD-L1-linked spatial decoupling of tumour-immune interactions in EBV-positive DLBCL

Abstract

EBV-positive diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma enriched in elderly patients, in which PD-L1 genomic gains cooperate with viral signalling to promote immune escape. However, the spatial mechanisms by which PD-L1 reshapes the tumour microenvironment remain unresolved. Here, we integrate genomic profiling with spatial transcriptomics, spatial proteomics, and single-cell RNA sequencing to resolve the tumour-immune architecture of EBV-positive DLBCL. PD-L1 gain tumours exhibit a striking decoupling of immune proximity and immune engagement: T cells accumulate in close proximity to tumour cells yet direct tumour-immune contact is largely absent. Tumour boundaries are enriched for cancer-associated fibroblasts and display transcriptional signatures of metabolic immune suppression, while tumour-proximal T cells exhibit pronounced exhaustion. Together, these findings reveal a PD-L1-driven spatial immune evasion architecture that permits immune infiltration while enforcing multilayered suppression through fibroblast-mediated exclusion, metabolic constraint, and T-cell dysfunction, ultimately preventing effective anti-tumour immunity in EBV-positive DLBCL.