GBP2 condensates promote ferroptosis to sensitize anti-PD-L1 immunotherapy in melanoma.

ABSTRACT: The mechanisms underlying the limited response to immune checkpoint blockade (ICB) remain unclear. One explanation is that tumors escape cytotoxic T cell killing by disrupting interferon-gamma (IFN-γ) signaling. Here we show that guanylate-binding protein 2 (GBP2), an IFN-γ-inducible molecule, functions as a general amplifier of T cell-mediated cytotoxicity by promoting ferroptosis in melanoma. GBP2 enhances STAT1 activation and suppresses SLC7A11, thereby sensitizing tumor cells to ferroptotic death. Upon IFN-γ stimulation, GBP2 undergoes phase separation through an intrinsically disordered region, forming condensates that sequester SHP1 and sustain STAT1 activation. Disrupting GBP2 phase separation impairs ferroptosis, accelerates tumor growth, and weakens T cell-driven tumor control. GB

SUBMITTER: Liu X 

PROVIDER: S-EPMC12847934 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature