A conserved pan-cancer transcriptional signature identifies human M-MDSCs and reveals a REL/NFKB1⁺ rMos immunosuppressive population

Myeloid-derived suppressor cells (MDSCs), particularly the monocytic subset (M-MDSCs), are important mediators of tumor immune evasion. However, their reliable identification across human cancers remains challenging because of the lack of specific and conserved molecular markers. Through computational discovery in breast cancer followed by experimental and single-cell transcriptomic validation across multiple human cancers, we identified a five-gene transcriptional signature comprising VCAN, APOBEC3A, CD300E, EREG, and FCN1 that supports the identification of human M-MDSCs. Application of this signature enabled higher-resolution characterization of M-MDSC heterogeneity and identified c-Rel-dependent monocytes (rMos) across multiple human cancers, with their presence further supported by protein-level detection of REL⁺CCR2⁺ rMos populations across six carcinomas. Single-cell transcriptomic analysis further revealed consistent co-expression of REL and NFKB1 within human rMos, suggesting coordinated NF-κB transcriptional regulation in this population. In lung adenocarcinoma, tumor-associated rMos displayed substantial transcriptional remodeling, with increased SPP1—a well-established mediator of tumor progression and immune suppression—emerging as a prominent feature of this population. Higher SPP1 expression was also associated with poorer overall survival in LUAD. Together, our findings establish a cross-cancer molecular framework for resolving human M-MDSCs, extend the characterization of rMos to human tumors, and identify REL/NFKB1 co-expression and SPP1 as prominent molecular features of tumor-associated rMos that warrant further mechanistic investigation.