Authors
Fan Xu, Min Li, Yuan Zhang, Zhi Xu, Qiming Yin, Sijia Zhang, Fei Wu, Yuyan Ma, Zhangjun Jia, Xiumei Wang, Jiachen Dong, Ziyu Zhou, Jian Jian Li, Xiao Li, Yanyan Zhang
Published in
Cell death & disease. Jul 11, 2026. Epub Jul 11, 2026.
Abstract
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.
PMID:
42436143
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.
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