Dynamic myeloid suppressor states in cancer and inflammation and their therapeutic potential.

PURPOSE OF REVIEW: Myeloid-derived suppressor cells (MDSCs) are central mediators of immune dysregulation in cancer, infection, and inflammatory diseases. This review highlights recent advances redefining MDSCs' biology, with a focus on their developmental origin, functional plasticity, and the signaling and metabolic networks that regulate their expansion and activity within the bone marrow and peripheral tissues.

RECENT FINDINGS: Single-cell and lineage-tracing studies demonstrate that MDSCs do not represent a discrete lineage but instead arise as dynamic functional states across the myeloid continuum during emergency myelopoiesis. These states encompass polymorphonuclear and monocytic subsets derived from both immature progenitors and reprogrammed mature myeloid cells under inflammatory conditions. Transcriptional regulators, including STAT3, C/EBPβ, and IRF8, coordinate their differentiation, while cytokine signaling, chemokine-mediated trafficking, and metabolic reprogramming sustain suppressive function within diseased tissues. Emerging evidence further implicates bone marrow niche-derived signals and microbial cues as critical modulators of MDSC expansion and recruitment.

SUMMARY: MDSCs are best understood as context-dependent myeloid states shaped by inflammatory and metabolic cues. Defining the regulatory checkpoints governing these transitions has important implications in hematological malignancies and inflammatory disorders. Emerging therapeutic strategies aimed at limiting MDSC recruitment, reprogramming suppressive myeloid states, or targeting their metabolic and signaling dependencies hold significant potential to enhance immunotherapy efficacy and restore immune homeostasis across cancer and inflammatory diseases.