TBL1XR1 mutations promoted tumor progression in diffuse large B-cell lymphoma through impairing nature killer...

TBL1XR1 is frequently mutated in diffuse large B-cell lymphoma (DLBCL), yet its functional impact on tumor microenvironment remains poorly defined. In this study, we characterized TBL1XR1 mutations in a cohort of 1842 newly diagnosed DLBCL patients, identifying mutations in 9.4% of cases (n = 173). These mutations correlated with clinically aggressive features, including older age (> 60 years), high-risk International Prognostic Index, enrichment in non-GCB subtypes, as well as inferior progression-free and overall survival. Mechanistically, TBL1XR1 mutations enhanced H3K27ac levels at the MYC promoter, increased MYC expression and subsequently up-regulated its immune-regulatory targets CD47 and PD-L1. This axis impaired natural killer (NK) cytotoxicity, facilitating immune escape and tumor progression. In a murine A20 B-lymphoma model, tumors harboring Tbl1xr1 mutations exhibited up-regulated MYC, CD47, and PD-L1 expression, resulting in NK cell dysfunction and tumor growth acceleration via the MYC-CD47/PD-L1 axis. Dual blockade of CD47 and PD-L1 restored NK cell-mediated tumor immunity, triggering rapid regression of Tbl1xr1-mutated tumors. Taken together, our findings identified TBL1XR1 mutations as a microenvironment-related mechanism of DLBCL progression and provided clinical rationale of co-targeting CD47 and PD-L1 to treat this genetically defined subset.