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

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. GBP2 also increases HMGB1 release from ferroptotic cells, promoting cytotoxic T cell infiltration. These findings identify GBP2 as a key mediator linking IFN-γ signaling to ferroptosis and demonstrate that enhancing this pathway can improve tumor responsiveness to ICB immunotherapy. The mechanisms underlying the limited response to immune checkpoint blockade (ICB) in most patients remain elusive. This study identifies GBP2 as a key enhancer of T cell-mediated ferroptosis and ICB efficacy through phase separation and STAT1 activation.