{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:57:15Z","timestamp":1791835035676,"version":"4.3.4"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Multiple myeloma (MM) is highly heterogeneous, with relapse occurring in the majority of cases, and recent advancements in single-cell RNA sequencing (scRNA-seq), sc-metabolism profiling, and bulk RNA-seq have facilitated the identification of cell subpopulations and metabolic reprogramming at the single-cell level, uncovering novel molecular mechanisms. This study aims to establish a multi-omics atlas of MM, characterizing the cell subpopulations and signaling pathways that drive immune evasion and disease progression. Additionally, sc-metabolic profiling identifies reprogramming patterns and informs therapeutic screening. We integrated scRNA-seq and bulk RNA-seq data using R to analyze immune and non-immune cell features and pathways in MM. Metabolic reprogramming was assessed via sc-metabolic profiling, and drug candidates were screened through multi-omics integration, with efficacy evaluated <jats:italic>in vitro<\/jats:italic> using CCK-8 assays, flow cytometry, Western blotting, and CalcuSyn software. Novel MM subpopulations were identified, including myeloma-activated hematopoietic stem cells and ISG15+ B cells, which correlated with survival and were validated by multiplex immunofluorescence. IFN-\u03b3 is primarily secreted by effector memory CD8+T cells, and IFN-\u03b1 is primarily secreted by non-classical monocytes, driving an IFN-\u03b3\/\u03b1-B2M feedback loop. Multi-omics identified four drug candidates, each demonstrating anti-tumor effects against myeloma cell lines.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1575079","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T05:26:30Z","timestamp":1757309190000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi-omics reveals immune features in immune and non-immune cells, an IFN-\u03b3\/IFN-\u03b1-B2M positive feedback loop, and targeted metabolic therapy in multiple 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