Metabolic Reprogramming of Vδ2 T cells in Multiple Myeloma and Hematological Malignancies

Vδ2 T cells are a cytotoxic T-cell subset with a natural ability to eliminate multiple myeloma (MM) cells expressing phosphoantigens (pAgs) and stress-induced ligands. However, in the bone-marrow tumor microenvironment (TME), they become dysfunctional, displaying anergy to pAgs and high immune-checkpoint expression. Whether this impairment also reflects TME-driven metabolic dysregulation remains unclear. In this study, we evaluated the metabolic fitness of Vδ2 T cells from the bone marrow (BM) of MM patients and compared them with BM samples from non-MM malignancies (non-MM), BM without pathological involvement (BM CTRL), and peripheral blood of healthy donors (PB CTRL). Vδ2 T-cell metabolism was compared with that of CD4, CD8, and Vδ1 T cells in each sample. Additionally, Vδ2 T cells were compared among MM, non-MM, and PB CTRL groups. Vd2 T cells were investigated at rest and after pAg mediated stimulation. At rest, BM-derived Vδ2 T cells from MM patients displayed reduced mitochondrial potential and increased glucose uptake compared with other BM T-cell subpopulations and PB CTRL. Similar but less pronounced alterations were observed in BM non-MM. Upon pAg stimulation, PB CTRL Vδ2 T cells showed robust proliferation and metabolic activation, whereas Vδ2 T cells from BM MM, and to a lesser extent BM non-MM, exhibited a markedly impaired metabolic response. IL15 supplementation improved both the metabolic and proliferative capacity of Vδ2 T cells from PB CTRL. These findings indicate that metabolic dysfunctions contribute to Vδ2 T-cell impairment in MM and support metabolic correction, such as IL15 supplementation, as a strategy to improve their antitumor potential.