{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T09:34:01Z","timestamp":1758188041501,"version":"3.44.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"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:sec><jats:title>Background<\/jats:title><jats:p>Multiple myeloma (MM) is characterized by extensive intratumoral heterogeneity and complex interactions within the bone marrow microenvironment, yet the cellular and molecular drivers of treatment resistance remain poorly defined. Protein tyrosine phosphatase receptor gamma (PTPRG) has emerged as a candidate tumor suppressor in various malignancies by antagonizing proliferative and survival signaling, but its functional and prognostic relevance in MM has not been established.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed 103,171 single\u2010cell transcriptomes from 18 MM samples (10 optimal responders [OR] and 8 suboptimal responders [SOR] to bortezomib\u2013melphalan\u2013prednisone) to investigate cell\u2010type composition, malignant plasma cell subclusters, and tumor\u2013microenvironment crosstalk. InferCNV was used to distinguish malignant plasma cells, which were further reclustered and correlated with bulk prognostic phenotypes. Differential expression, pathway enrichment, transcription\u2010factor activity, pseudotime trajectory, and ligand\u2013receptor interaction analyses were performed. Finally, bulk datasets (GSE9782, GSE2658, MMRF-CoMMpass) and <jats:italic>in vitro<\/jats:italic> knockdown assays in U266 and NCI-H929 cells were used to validate the prognostic and functional role of PTPRG.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eleven major cell types were annotated, with plasma cells, T\/NK cells, and CD14<jats:sup>+<\/jats:sup> monocytes predominating; SOR samples exhibited an expanded plasma\u2010cell fraction and reduced T\/NK, CD14<jats:sup>+<\/jats:sup> monocyte, pre-B, and HSPC populations. Among 35,944 malignant plasma cells, five subclusters were defined; one subcluster (MalPlasma3) was enriched in SOR samples and harbored 93.1% of cells associated with poor survival. MalPlasma3 and \u201cworse\u2010survival\u201d cells showed activation of stemness, E2F\/MYC targets, and G2M checkpoint pathways, driven by transcription factors E2F8, E2F7, FOXM1, E2F1, and TIMELESS. Pseudotime analysis revealed a bifurcating differentiation toward a resistant phenotype, accompanied by upregulation of cell\u2010cycle and proliferation modules. In the OR group, enhanced cytotoxic features in NK, effector, and na\u00efve T cells, along with IGF1\u2013IGF1R and IFNG\u2013IFNGR signaling, suggested a supportive microenvironment. In contrast to the known role as a tumor suppressor in solid and hematologic cancers, our integrative analyses identified PTPRG among seven stemness\u2010related genes upregulated in MalPlasma3 and poor\u2010survival cells, which was echoed in the observed reduced cell viability and increased apoptosis in MM cell lines following siRNA\u2010mediated PTPRG knockdown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This single\u2010cell multi\u2010omic dissection implicates a proliferative, stem\u2010like MalPlasma3 subcluster and identified PTPRG as a key mediator of drug resistance and poor outcome in MM, offering novel prognostic biomarkers and therapeutic targets.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1658028","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T05:33:33Z","timestamp":1758173613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell profiling uncovers PTPRG-driven stemness in malignant plasma cells and signatures of treatment failure in multiple 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