Abstract Background: B-cell lymphoma progression from indolent to aggressive disease involves profound disruption of the normal spatial architecture within the tumor microenvironment (TME). Most spatial profiling efforts have focused on isolated lymphoma subtypes or correlating TME compositions with clinical factors (Colombo, 2022; Sharma, 2025; Dai, 2025; Autio, 2025). This fragmented approach limits understanding of lymphomagenesis as an evolutionary spatial process. We utilized single cell spatial transcriptomics and proteomics across a diverse array of subtypes to understand B-cell lymphomas as a continuous trajectory of structural evolution, architectural rewiring, and increasing clinical aggressiveness. Methods: We used the Xenium platform to profile 165 tissue cores from a pan-lymphoma tissue microarray, mapping 2. 5 million cells. The cohort spanned reactive tissues, indolent lymphomas, aggressive lymphomas (e. g. , DLBCL, MCL), and Hodgkin-associated diseases. We identified 16 refined cell states and constructed an atlas-wide neighborhood niche model. Spatially weighted ligand-receptor scoring mapped intercellular communication across the disease spectrum. Proteomic validation was performed using sequential IF (Lunaphore). Results: Our pan-lymphoma atlas identified 18 specialized spatial niches grouped into 7 broader families, revealing a progressive spatial continuum from reactive B-cell states to highly proliferative malignant programs. Early indolent tissues (PTGC, FL1) are dominated by non-cycling FCMR/TCL1A B-cells and maintain a balanced mixture of reactive and transformed germinal center (GC) architectures. Conversely, aggressive lymphomas (FL3A, GC DLBCL) are characterized by the near-complete dominance of a cycling GC niche. ABC DLBCLs uniquely accumulate a distinct myeloid-inflammatory niche enriched with cytotoxic/NK-like T-cells and cycling myeloid states. Crucially, we discovered "niche-conditioned" transcriptional rewiring, wherein identical immune and stromal cell states acquire distinctly different gene expression profiles depending on their specific spatial neighborhood. Furthermore, spatial ligand-receptor mapping showed the trajectory toward aggressive disease is marked by loss of classical, organized stromal and endothelial homing signals (CCL19/CCL21-CCR7). In their place, aggressive tumors establish highly inflammatory, myeloid- and T-cell-driven recruitment networks, including robust CCL5-CCR5, CXCL16-CXCR6, and FASLG-FAS interactions. Conclusions: Evaluating the TME across the lymphoma spectrum demonstrates that transformation to aggressive B-cell lymphoma involves profound architectural and transcriptional rewiring. As tumors progress, malignant B cells abandon organized stromal homing networks and reprogram neighboring immune cells to establish localized, inflammatory, and immunosuppressive spatial niches. Generative AI tools were used edit and revise text used in this abstract. Citation Format: Joseph Lownik, Larry Milshteyn, Anton Luis. Villamejor, Akil Merchant. Spatially resolved single cell atlas reveals niche-driven transcriptional rewiring across a B-cell lymphoma continuum and gives insights into transformation abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr A057.
Lownik et al. (Wed,) studied this question.