Role of EVs in the MM microenvironment. MM cells reside in the hypoxic BM milieu, which will trigger MM EV release. These EVs will stimulate angiogenesis by delivering pro-angiogenic cargo including VEGF, miR-135b and piRNA-823, which will trigger proliferation and tube formation in ECs. Osteolysis will be activated by inducing osteoclast proliferation and activation through the delivery of EV cargo (AREG, IL32 and sXBP1) and by blocking osteoblast differentiation and activity through inhibitory cargo such as AREG, DKK1, lncRUNX2-AS1, and miR-129-5p. Moreover, osteoblasts are stimulated to secrete cMet and IL11 for the osteoclasts. Immune suppression is induced by the presence of CD73 and CD39, and activation of MDSC and TAMs via miR-1305 EV delivery, who in turn will inhibit NK- and T-cell proliferation. MM EVs have a direct impact on T cells by inhibiting CD8 activation and inducing T regulatory cell expansion. Direct effects on NK cells are more inconclusive and only occur after treating MM cells with cytotoxic compounds, releasing “chemoexosomes” (depicted with a ∗). IFNγ is released in response to chemoexosomes, but NK activation is uncertain. These chemoexosomes also contain cell cycle proteins and acid SMase, thereby inducing auto-resistance. Finally, MM cells trigger BMSC to transform into CAFs by delivering mir-146a, mir-21, WWC2, CD166, and CD44 as EV cargo. Transition toward CAFs is accompanied by miR-27b-3p and miR-214-3p upregulation. CAFs in turn will release growth and survival cargo to MM cells, containing IL6, FN, PSMA3, Circ_0007841, Bcl-XL, miR-10, miR-214-3p, miR-5100 and LINC00461. They will also stimulate TAMs via delivery of miR-let-7c. A downward arrow indicates less expression of specific cargo in tumoral EVs. This figure was created with biorender.com.