Patrizia Mondello, Alisa Sadekova, Ksenia Fede, Surendra Dasari, Wesley Au, Moritz Binder, Kirill Kriukov, Mark Meerson, Joseph Novak, Zhi-Zhang Yang, Brianna Negaard, Ekaterina Postovalova, Jose Villasboas, Daniil Wiebe, Anastasiia Shvyrkova, Emmanuel Contreras Guzman, Nikita Kotlov, Sargis Margaryan, Alexander Nesmelov, Aleksander Sarachakov, Arman Petrosyants, Alexander Bagaev, Yucai Wang, Anne Novak, Carla Casulo, Thomas Habermann, Eric Hsi, Matthew Maurer, James Cerhan, Nathan Fowler, Rebecca King, Mark Shlomchik, Harinder Singh, Philippe Armand, Laura Pasqualucci, Richard Burack, Stephen Ansell
Germinal center (GC)-derived lymphomas arise within a specialized immune ecosystem, yet whether malignant cells direct its remodeling remains unclear. Integrating genomic, transcriptomic, spatial, and functional analyses across follicular lymphoma and diffuse large B-cell lymphoma, we define a developmental framework linking malignant B-cell differentiation state to tumor microenvironment (TME) organization. Rather than segregating by histology, lymphomas align along a shared differentiation continuum in which proliferative dark zone (DZ) states associate with immune-depleted TMEs, whereas post-GC/memory B-cell (MBC) states drive inflamed but immunosuppressed TMEs. Spatial profiling reveals collapse of GC architecture and emergence of suppressive myeloid niches along this trajectory. Single-cell lineage reconstruction uncovers a DZ-to-MBC developmental axis underlying lymphoma evolution. Genetic reprogramming in vivo demonstrates that malignant differentiation state is sufficient to instruct TME remodeling. Collectively, these findings establish malignant differentiation state as a causal determinant of immune architecture across GC-derived lymphomas and identify lineage-directed immune reprogramming as a potential therapeutic strategy.