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Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB–mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype. We demonstrated significantly higher Treg induction, expansion, and proliferation triggered by WM cells, compared with their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-cell–to–T-cell cross talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis that supports WM cell–Tregs interaction. Our findings demonstrate the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.

Within the context of precision medicine, the scientific community is giving particular attention to early diagnosis and intervention, guided by non-invasive methodologies. Liquid biopsy (LBx) is a recent laboratory approach consisting of a non-invasive blood draw, which allows the detection of information about potential prognostic factors, or markers to be used for diagnostic purposes; it might also allow the clinician to establish a treatment regimen and predict a patient’s response. Since the discovery of circulating tumor cells (CTCs) in the nineteenth century, the possibility of integrating LBx into clinical practice has been explored, primarily because of its safeness and easy execution: indeed, compared to solid biopsy, sampling-related risks are less of a concern, and the quickness and repeatability of the process could help confirm a prompt diagnosis or to further corroborate the existence of a metastatic spreading of the disease. LBx’s usefulness has been consolidated in a narrow range of oncological settings, first of all, non-small cell lung carcinoma (NSCLC), and it is now gradually being assessed also in lymphoproliferative diseases, such as acute lymphocytic leukemia (ALL), B-cell lymphomas, and multiple myeloma. The present review aims to summarize LBx’s overall characteristics (such as its advantages and flaws, collection and analysis methodologies, indications, and targets of the test), and to highlight the applications of this technique within the specific field of B-cell malignancies. The perspectives on how such a simple and convenient technique could improve hemato-oncological clinical practice are broadly encouraging, yet far from a complete integration in routine clinical settings.