Single-nucleus and spatial transcriptomics analyses reveal interplay between evolutionary dynamics and energy metabolism in primary cardiac lymphoma.

Primary cardiac lymphoma (PCL), a rare B-cell non-Hodgkin's lymphoma, has shown a rising incidence, yet the lack of clarity regarding its molecular basis continues to hinder the development of effective targeted therapies. In this study, we utilized single-nucleus RNA sequencing and Visium CytAssist spatial transcriptomics in two patients with PCL to examine the metabolic and immune landscape of PCL. Our data implicate chromosomal instability (CIN) as a potential driver of disease progression, likely by modulating cellular sensitivity to metabolic stress. Single-cell analysis identified five distinct malignant B-cell states, including a B3 subset defined by subclonal diversification and enriched fatty acid metabolism-MAPK signaling. NFYA was also noted as a transcription factor potentially involved in this lipid reprogramming. Spatial observations suggest that B3 cells may contribute to an immunosuppressive microenvironment, with the CD44-LGALS9 axis acting as a possible mediator of endothelial cell remodeling and T-cell suppression. Ultimately, this study provides fresh insights into the clonal evolution and metabolic adaptations of PCL. These findings suggest that fatty acid metabolic reprogramming and CD44-LGALS9-mediated immune evasion play roles in tumor maintenance within the cardiac environment, offering a preliminary basis for future targeted therapeutic intervention.