Background <p>A comprehensive single-cell map of Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) that profiles malignant B-cell heterogeneity and TME immune dynamics is urgently needed.</p> Methods <p>We generated single-cell RNA sequencing (scRNA-seq) profiles of 12,709 cells from a study of three ABC-DLBCL patients which was deposited in the GSE1824364. Malignant B-cell subsets were survival-linked by Scissor against two bulk ABC cohorts. R-loop scores, pseudotime, immune re-clustering, and cell–cell communication were computed; poor-outcome driver was validated by Immunohistochemistry (IHC).</p> Results <p>We identified five major immune cell types and 2350 malignant B cells. Malignant B cells showed upregulation of oxidative phosphorylation, MYC targets, and IL-2/STAT5 signaling. Reclustering revealed a poor-prognosis malignant B cells subpopulation enriched for inflammatory and immunosuppressive pathways. Pseudotime analysis indicated malignant B cells occupied later differentiation states with heightened B cell activation and immune evasion signaling. Subclustering of immune cells uncovered diverse T and myeloid populations, with CD8⁺T cells and macrophages being predominant. Cell–cell communication analysis revealed that poor-prognosis malignant B cells uniquely activated CD70-CD27 signaling, promoting Treg expansion and T cell exhaustion, while good-prognosis cells engaged T cells via ICAM1. Integrative analysis across datasets identified transmembrane immune signaling adaptor (TYROBP) as a key gene associated with poor survival, tumor aggressiveness, and Treg infiltration. IHC validation confirmed that TYROBP is significantly overexpressed in ABC-DLBCL tissues.</p> Conclusion <p>Our study uncovered TYROBP as a readily detectable biomarker and a tractable target to counteract the dual drivers of resistance in ABC-DLBCL.</p>