Beyond EMT: Mesenchymal drift as an emerging driver of stromal-immune reprogramming in prostate cancer

Abstract

Summary Cellular plasticity within the tumor microenvironment (TME) extends far beyond classical epithelial-mesenchymal transition (EMT). Emerging evidence indicates that diverse non-epithelial cell populations, including macrophages, endothelial cells, pericytes, adipocytes, and fibroblasts, undergo a progressive and often partial reprogramming toward mesenchymal-like states during tumor progression. We conceptualize this broader phenomenon as mesenchymal drift (MD), a trans-lineage adaptive process characterized by erosion of lineage-specific identity, acquisition of extracellular matrix-remodeling capacity, enhanced migratory potential, and epigenetic stabilization of pro-fibrotic and immunosuppressive programs. In prostate cancer (PCa), MD provides a conceptual framework for interpreting stromal-immune remodeling across epithelial, endothelial, immune, adipose, and fibroblastic compartments. Macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndoMT), pericyte-to-fibroblast transition (PFT), and adipocyte mesenchymal transition (AMT) collectively expand the pool of cancer-associated fibroblasts, promote matrix stiffening, induce vascular dysfunction, and reinforce immune evasion. These processes are proposed to be driven by overlapping signaling networks—including TGF-β/Smad, Wnt/β-catenin, Hippo/YAP-TAZ, PDGF, and inflammatory NF-κB/STAT3 pathways—and are stabilized by DNA methylation, histone modifications, and non-coding RNAs. Clinically, MD-associated transcriptional signatures correlate with aggressive phenotypes, metastasis, and therapy resistance across solid tumors, including PCa, highlighting their potential as prognostic biomarkers and therapeutic targets. Pharmacologic inhibition of key MD drivers, epigenetic reprogramming strategies, and combinatorial approaches with immunotherapy represent promising translational avenues. By integrating diverse mesenchymal transition processes under a unified conceptual framework, this review positions mesenchymal drift as a unifying axis of stromal-immune reprogramming in prostate cancer and underscores its significance for next-generation therapeutic strategies.