CLL-derived exosomes have a paracrine effect on stromal cells residing in the TME. The transfer of exosomal cargoes (miRNA and proteins) to target cells (bone marrow, BM-MSCs, and endothelial cells) induces an inflammatory CAF phenotype in these cells that assume an aberrant stimulatory, protumoral role (increased angiogenesis, release of pro-survival chemokines/cytokines). In parallel, CLL-derived exosomes can act as decoy receptors for rituximab, thus representing a potential drug escape mechanism in the TME. BM, bone marrow; NK-κB, nuclear factor κB.