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Figure 2. Proposed tumor metabolic modulation exerted by EVs derived from TILs and MSCs. Small circles represent EVs and exosomes from the origin cells. Suggested tumor metabolic targets of the microparticles cargo are depicted and represented by dotted arrows (red: negative regulation; green: positive regulation). A: Reduced tumor glycolysis could be achieved by miRs within NK-derived EVs by downregulating HIF-1α (miR-186) and HK (miR-125b-5p and miR-199a-5p, as detailed). Conversely, increased glycolysis may be epigenetically induced by miR-21 and miR-1180 within hBM-MSC exosomes at specific regulatory checkpoints. Expected glycolytic targets of miRs within NK and h-BM-MSC-derived EVs and exosomes. Depending on the EV-secreting cell and specific miR cargo, both glycolysis downregulation (at HK level, by miR-186, miR-125b-5p, and miR-199a-5p from NK-derived EV, and at FBP1 and PDH levels, by the action of miR-21 contained in h-BM-MSC EVs) and upregulation (at HK, PK, PDK, and LDH levels through a miR-1180 modulation mediated by h-BM-MSC EVs) can be observed; B: cytotoxic T lymphocytes (CD8⁺) can release miR-765 within exosomes. This miRNA could decrease the lipid content of tumor cells through PLP2 downregulation. Inversely, the onco-miR-21 contained in the exosomes of h-BM-MSC may increase the expression of the fatty acid translocase (CD36) in tumor cells, leading to enhanced exogenous uptake and intracellular levels of the energetic supply of phospholipids, neutral lipids, and TAG. Additionally, increased intracellular levels of the enzymes ACC and FASN related to lipid synthesis and FABP5 related to tumor progression in many cancers (reviewed in 26) may also be observed due to the miR-21 within h-BM-MSC exosomes. C: helper T lymphocytes (CD4⁺) release exosomes enriched in miR-155-5p, which could negatively regulate the expression of the GATM gene that encodes glycine amidinotransferase, an enzyme involved in creatine synthesis; D: EVs derived from B lymphocytes contain CD39 and CD73, which are proteins involved in the phosphohydrolysis of ATP and ADP to AMP, producing ADO. Inversely, pro-tumoral roles of lactate and miR-1180 within h-MSC microparticles could be induced by increased ATP production and migratory capacity as a result of a modulation of the oxidative (E) or glycolytic (A) metabolism, respectively; E: hMSLC-EVs may provide Glutamine and further converted in α-ketoglutarate, replenishing the citric acid cycle (TCA) and fueling the metabolism of cancer cells. Similarly, a possible conversion of the exosomal lactate from hAT-MSC exosome to pyruvate may also replenish the TCA and enhance the ATP production by the mitochondrial complexes, thus boosting the tumor cell migration in an uptake mediated by the MCT-1 transporter. EVs: Extracellular vesicles; TILs: tumor-infiltrating lymphocytes; ACC: acetyl-CoA carboxylase; ADO: adenosine; ADP: adenosine diphosphate; AMP: adenosine monophosphate; ATP: adenosine triphosphate; CD4: T-cell surface glycoprotein CD4; CD8: a cluster of differentiation 8; CD36: fatty acid translocase; CD39: ectonucleoside triphosphate diphosphohydrolase 1; CD73: ecto-5′-nucleotidase; FABP5: fatty acid binding protein 5; FASN: fatty acid synthase; FBP1: fructose-1,6-bisphosphatase; GATM: glycine amidinotransferase; hAT-MSC: human adipose tissue mesenchymal stem cell; hBM-MSC: human bone marrow mesenchymal stem cell; HIF-1𝛼: hypoxia-inducible factor 1-alpha; HK: hexokinase; hMSLC: human mesenchymal stem-like cell; LDH: lactate dehydrogenase; MCT-1: monocarboxylate transporter 1; miR: micro-RNA; NK: natural killer; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; PK: pyruvate kinase; PLP2: proteolipid protein 2; TAG: triacylglycerol; TCA: tricarboxylic acid cycle; I-IV: mitochondrial respiratory complexes. (Created with BioRender).