{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:01:52Z","timestamp":1788886912638,"version":"build-2803163510"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004331","name":"Johnson and Johnson","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004331","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Multiple myeloma (MM) develops within a profoundly immunosuppressive bone marrow (BM) microenvironment. CD38, a multifunctional ectoenzyme highly expressed on malignant plasma cells, contributes to this niche by degrading nicotinamide adenine dinucleotide (NAD\n                      <jats:sup>+<\/jats:sup>\n                      ) into ADPR, which fuels adenosine (ADO) production through CD38\/CD203a\/CD73 enzymatic pathway. CD38_targeting monoclonal antibodies (mAbs), including daratumumab (DARA) and isatuximab (ISA), exert antitumor activity through direct cytotoxicity and immune modulation; however, resistance to these agents remains a major clinical challenge. Understanding how CD38 enzymatic activity and adenosinergic metabolism evolve during therapy is essential for improving treatment efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study investigates (i) the enzymatic functions of CD38, (ii) the\n                      <jats:italic>in vitro<\/jats:italic>\n                      effects of DARA and ISA on CD38_mediated NAD\n                      <jats:sup>+<\/jats:sup>\n                      degradation in primary MM cells and a representative MM cell line, and (iii) the\n                      <jats:italic>in vivo<\/jats:italic>\n                      dynamics of ADO and its metabolite inosine (INO) in BM and peripheral blood (PB) plasma from MM patients receiving DARA monotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      , both DARA and ISA promoted NAD\u207a degradation with accumulation of ADPR.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , ADO concentrations in BM plasma remained consistently in the micromolar range and declined only modestly during treatment, whereas INO progressively increased, leading to a gradual attenuation of the BM -PB gradient. These findings indicate that adenosinergic metabolism remains active during DARA therapy, likely sustained by reduced CD38 expression due to antibody_driven internalization or microvesicle (MV) release, together with adenosine deaminase (ADA) -mediated ADO degradation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Despite CD38_targeted therapy, ADO concentrations in the BM remain well above the activation thresholds of P1 purinergic receptors, suggesting persistent adenosinergic immunosuppression. This sustained ADO production may contribute to a tolerogenic BM niche that promotes immune evasion and therapeutic resistance. These results support the rationale for combining CD38_directed antibodies with agents targeting adenosinergic signaling to enhance antitumor immunity and improve clinical outcomes in MM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1769281","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T05:55:09Z","timestamp":1777442109000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Modulating CD38 enzymatic activity during antibody-based immunotherapy in multiple myeloma: a basic science perspective"],"prefix":"10.3389","volume":"17","author":[{"given":"Alberto L.","family":"Horenstein","sequence":"first","affiliation":[{"name":"Laboratory of Immunogenetics, Department of Medical Sciences","place":["Turin, Italy"]},{"name":"CeRMS, University of Torino","place":["Turin, Italy"]},{"name":"Fondazione Ricerca Molinette","place":["Turin, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine A.","family":"Frerichs","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC Location, Vrije Universiteit Amsterdam","place":["Amsterdam, Netherlands"]},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology","place":["Amsterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo C.","family":"Faini","sequence":"additional","affiliation":[{"name":"Immunogenetics and Transplant Biology Service, University Hospital \u201cCitt\u00e0 della Salute e della Scienza di Torino\u201d","place":["Turin, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels W. 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