Abstract

Multiple myeloma (MM) orchestrates immune evasion by subverting natural killer (NK) cell function. CD48, one of the most abundant NK-ligands on MM cells, paradoxically enhances NK-cell activation yet is associated with high-risk cytogenetics and poor patient survival. We integrated multi-omics (bulk and single-cell RNA-seq, ATAC-seq), genome-wide CRISPR-KO/a screens, and machine learning to dissect CD48 regulation and function. In human MM and Vκ*MYC mice scRNA-seq datasets, NK cells exhibit stepwise increases in inflammatory and exhaustion signatures and loss of cytotoxic potential as disease progresses. In vitro co-culture assays show CD48 overexpression on MM enhances initial NK-cell cytotoxicity and cytokine secretion, whereas chronic exposure leads to ex vivo NK dysfunction. In vivo, CD48-overexpressing Vκ*MYC tumors progress more slowly and extend host survival, while NK-cell depletion accelerates disease. These findings support a context-dependent role for CD48, potentiating acute NK responses while coexisting with chronic NK exhaustion, and suggest strategies to modulate CD48 for therapeutic benefit. ### Competing Interest Statement A.P.W. is a scientific co-founder and equity holder in Seen Therapeutics; equity holder in Indapta Therapeutics; received licensing fees from Deverra Therapeutics. C.S.M. has served on the Scientific Advisory Board of Adicet Bio and discloses consultant/honoraria from Genentech, Nerviano, Secura Bio and Oncopeptides, and research funding from EMD Serono, Karyopharm, Sanofi, Nurix, BMS, H3 Biomedicine/Eisai, Springworks, Abcuro, Novartis and OPNA. The other authors declare no relevant competing interests. Multiple Myeloma Research Foundation Fellowship Multiple Myeloma Research Foundation Translational Accelerator Grant UCSF Stephen and Nancy Grand Multiple Myeloma Translational Initiative Myeloma Solutions Fund Chan Zuckerberg Biohub Investigator Award Blood Cancer United (formerly known as Leukemia and Lymphoma Society) Translational Research Program de Gunzburg Myeloma Research Foundation The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation NCI, P30CA082103