Coevolution of TME and cancer cells during lymphoma progression. Lymphoma cells induce a progressive reprogramming of the germinal center microenvironment that may imply initial expansion of cell subpopulations (eg, CD4⁺ T-follicular helper cells), recruitment and phenotypic reprogramming (eg, FRC and fibroblasts into CAFs) and wipe out of functions (eg, CD8⁺ cytotoxic T cells becoming exhausted). A common pattern of this coevolution for most DLBCL subtypes is the progressive loss of TME cellular diversity and components of the APPP, whereas lymphoma cells gain in proliferation capacity. In the initial stages, the TME provide several external checkpoints for lymphoma progression (represented by thicker inhibitory vs stimulatory arrows), whereas lymphoma cells developed evasion mechanisms (genetic, epigenetic, metabolic) that affect the cellular composition and/or functionality of TME cells. Later stages are accompanied by profound changes in the TME with little resemblance to the organ of origin. At this stage, the TME provides stronger support to lymphoma growth (represented by thicker stimulatory vs inhibitory arrows). Aging tissues are characterized by attenuation of checkpoints (eg, immunesenescence) and increased lymphoma supporting mechanisms (eg, cellular and ECM inflammatory changes) that may facilitate lymphoma development and progression. ECM, extracellular matrix; FDC, follicular dendritic cells; FRC, fibroblastic reticular cells; MDSC, myeloid-derived suppressor cells; TAM, tumor-associated macrophages; TAN, tumor-associated neutrophils; VEC, vascular endothelial cells; VLC, vascular lymphatic cells.