{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:29:44Z","timestamp":1785403784639,"version":"3.56.0"},"reference-count":19,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union, Next Generation EU","award":["PNRR-MAD-2022-12376660"],"award-info":[{"award-number":["PNRR-MAD-2022-12376660"]}]},{"award":["PNRR-MAD-2022-12376660"],"award-info":[{"award-number":["PNRR-MAD-2022-12376660"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"name":"My First Airc Grant","award":["24534 (2021\/2025)"],"award-info":[{"award-number":["24534 (2021\/2025)"]}]},{"name":"PRIN 2022","award":["20229JM25N"],"award-info":[{"award-number":["20229JM25N"]}]},{"name":"PRIN PNRR 2022","award":["P2022E2JSK"],"award-info":[{"award-number":["P2022E2JSK"]}]},{"name":"PRINN PNRR 2022","award":["P202282S5M-PRO-MM-1"],"award-info":[{"award-number":["P202282S5M-PRO-MM-1"]}]},{"name":"European Commission Mission Cancer","award":["101097094"],"award-info":[{"award-number":["101097094"]}]},{"name":"Sicilian MicronanoTech Research And Innovation Center","award":["ECS00000022 CUP B63C22000900006"],"award-info":[{"award-number":["ECS00000022 CUP B63C22000900006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple myeloma (MM) develops through asymptomatic precursor stages characterized by progressive remodeling of the bone marrow (BM) immune microenvironment and disruption of bone homeostasis. To delineate changes in natural killer (NK) cell states during disease evolution, we investigated coordinated immune-tumor remodeling by integrating NK cell functional states with plasma cell-intrinsic susceptibility programs derived from CRISPR-based screens across healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed MM patients. The integration of NK cell state-associated gene signatures with plasma cell transcriptional programs revealed stage-specific co-variation between immune and tumor compartments. Public single-cell RNA sequencing datasets were interrogated to resolve NK cell heterogeneity, identifying cytotoxic CD56dim and regulatory CD56bright subsets. NK cell dynamics displayed stage-dependent changes, with early expansion followed by the contraction of CD56dim cells in BM, whereas CD56bright cells showed predominantly compositional remodeling. Within the CD56bright subset, transcriptional changes included an increased expression of KLRC1 (encoding NKG2A), subsequently validated by multiparametric flow cytometry. In parallel, plasma cell programs associated with NK sensitivity progressively decreased along disease stages, supporting tumor adaptation to immune pressure. The NKG2A ligand HLA-E displayed selective expression within CD16+ monocytes and followed a distinct variable pattern across disease stages, highlighting a microenvironmental contribution to NK cell regulation. Collectively, these findings indicate a coordinated process of immune-tumor co-evolution, characterized by dynamic remodeling of NK cell states and plasma cell susceptibility, with the NKG2A\u2013HLA-E axis emerging as a central interface during MM progression.<\/jats:p>","DOI":"10.3390\/ijms27114682","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T16:06:08Z","timestamp":1779465968000},"page":"4682","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coevolution of NK and Tumor Cell States Along Multiple Myeloma Progression from Precursor Conditions"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2759-3646","authenticated-orcid":false,"given":"Cristina","family":"Aquilina","sequence":"first","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Romano","sequence":"additional","affiliation":[{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"},{"name":"Department of Surgical, Oncological and Stomatological Disciplines (DICHIRONS), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2541-4619","authenticated-orcid":false,"given":"Anna Maria","family":"Corsale","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Biondo","sequence":"additional","affiliation":[{"name":"Hematology Section, Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8251-7537","authenticated-orcid":false,"given":"Maria","family":"Speciale","sequence":"additional","affiliation":[{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"},{"name":"Department of Surgical, Oncological and Stomatological Disciplines (DICHIRONS), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Tofacchi","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1973-0540","authenticated-orcid":false,"given":"Marta","family":"Di Simone","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Gigliotta","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Dieli","sequence":"additional","affiliation":[{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"},{"name":"Department of Surgical, Oncological and Stomatological Disciplines (DICHIRONS), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Avellone","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0261-202X","authenticated-orcid":false,"given":"Angelo","family":"Toscano","sequence":"additional","affiliation":[{"name":"General Orthopedics, IRCCS Rizzoli Orthopedic Institute, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Camarda","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Romano","sequence":"additional","affiliation":[{"name":"Hematology Section, Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Cambria","sequence":"additional","affiliation":[{"name":"Hematology Section, Department of General Surgery and 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1522-4504","authenticated-orcid":false,"given":"Cirino","family":"Botta","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1002\/ajh.26590","article-title":"Multiple myeloma: 2022 update on diagnosis, risk stratification, and management","volume":"97","author":"Rajkumar","year":"2022","journal-title":"Am. 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Bone Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1158\/1078-0432.CCR-10-1066","article-title":"The Progression from MGUS to Smoldering Myeloma and Eventually to Multiple Myeloma Involves a Clonal Expansion of Genetically Abnormal Plasma Cells","volume":"17","author":"Vidriales","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Portale, F., and Di Mitri, D. (2023). NK Cells in Cancer: Mechanisms of Dysfunction and Therapeutic Potential. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119521"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100109","DOI":"10.1016\/j.pscia.2026.100109","article-title":"Mechanisms of Tumor Cell Evasion from NK Cell-Mediated Killing and Advances in NK Cell-Based Cancer Immunotherapy","volume":"4","author":"Zheng","year":"2026","journal-title":"Pharm. Sci. 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