PET imaging enables direct evaluation of ferroptosis in HCC synergistically induced by anti-PD-L1 and Olaparib

Abstract The efficacy of PET image-guided immune checkpoint inhibitor-based therapy in hepatocellular carcinoma (HCC) management is limited by the lack of direct monitoring of therapeutic response. A key challenge is the mismatch between the therapeutic pathway and the imaging target, which hinders the accurate assessment of treatment outcomes. We addressed this challenge by combining anti-PD-L1 immunotherapy with Olaparib, a strategy that promotes ferroptosis in BRCA wild-type HCC by suppressing SLC7A11, thus allowing for therapeutic response evaluation via [ 18 F]FASu PET imaging of SLC7A11 expression. The combination treatment resulted in a 57% reduction in tumor volume, accompanied by decreased Ki-67 expression and increased levels of γ-H2AX and 8-OHdG. [ 18 F]FASu PET imaging revealed significantly lower SUVmax and tumor-to-background ratios in the combination group, correlating with SLC7A11 downregulation. Mechanistically, GPX4 downregulation, glutathione (GSH) depletion and elevated malondialdehyde (MDA) levels confirmed the activation of ferroptosis. Notably, no therapeutic or imaging response was observed in immunodeficient models. Thus, the SLC7A11-targeted PET tracer [ 18 F]FASu offers a clinically translatable biomarker for monitoring treatment efficacy, establishing a novel theragnostic paradigm that directly evaluates treatment response via PET imaging.