Oncogenic super-enhancer activation of TKT orchestrates metabolic reprogramming and immunosuppressive remodeling in prostate cancer

Here, we identify the non-oxidative pentose phosphate pathway enzyme transketolase (TKT) as a central effector in this oncogenic axis. Integrative epigenomic profiling of patient-derived tissues and prostate cancer models reveals tumor-specific activation of a distal super-enhancer that engages MYC to drive TKT transcription.

Beyond its canonical metabolic role, TKT promotes prostate tumor growth through suppressing interferon-stimulated gene expression by regulating R-loop dynamics. This suppression enhances CXCL6/CXCR2-mediated recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), thereby establishing a profoundly immunosuppressive tumor microenvironment. TKT depletion abrogates tumor progression in multiple murine models, diminishes PMN-MDSC infiltration, and restores CD8⁺ T cell cytotoxic function.