RelB/ILF2-GM-CSF loop sustains tumor-MDSC communication in prostate cancer immunosuppression.

Prostate cancer (PCa) exhibits an immune "cold" tumor microenvironment (TME) with significant enrichment of immunosuppressive myeloid-derived suppressor cells (MDSCs), which contribute to tumor progression and poor responses to immune checkpoint blockade (ICB). Although extensively studied, the precise mechanism underlying the tumor-intrinsic signals that educate and sustain the expansion and immunosuppressive function of MDSCs remains unelucidated. Here, we identify a previously unrecognized function of RelB by which nuclear interaction with ILF2 restricts ubiquitin-mediated degradation and sustains nuclear stability of RelB, thereby enhancing RelB-mediated CSF2 transactivation and enhanced GM-CSF (granulocyte-macrophage colony-stimulating factor) production and secretion. The secreted GM-CSF, in turn, promotes RelB nuclear accumulation, forming a feed-forward loop for sustaining GM-CSF generation. In MDSCs, GM-CSF activates STAT3-mediated MDSC expansion and immunosuppression. Disruption of RelB/ILF2 complex attenuates GM-CSF-driven MDSC expansion, restores CD8⁺ T cell-mediated antitumor activity, and inhibits tumor growth. In addition, a RelB-targeting peptide SN52 sensitizes PCa tumors to PD-1 blockade therapy. Collectively, our findings identify the RelB/ILF2-GM-CSF loop as a central regulator of MDSC-mediated immunosuppression, which may be targeted to improve PCa response to ICB.