Abstract 5349: Ferroptosis as a determinant of prognosis and response to immunotherapy in liver cancer

Abstract Background & aims: Ferroptosis, a regulated cell death mechanism driven by iron-dependent lipid peroxidation, is important for survival of cancer cells due to the increased vulnerability of fast-growing cancer cells to oxidative stress. However, its impact on clinical outcomes and treatment responses is not well understood. Our goal is to explore ferroptosis' contribution to liver cancer, focusing on its association with clinical outcomes, specifically incidence rates in high-risk cirrhotic patients, overall survival, and responsiveness to immunotherapy in HCC patients. Methods: Utilizing gene expression signature reflecting ferroptosis from liver cancer cells, we integrated gene expression profiles from patients with cirrhosis and liver cancer and from liver cancer cells under ferroptosis. To categorize patients, we developed a genomic predictor and applied it to gene expression data from a cirrhosis cohort (n=216) and large liver cancer cohorts (n=1390). Comprehensive statistical and informatics analyses were conducted to evaluate clinical significance, including overall survival and responses to standard treatments such as sorafenib and immunotherapy with atezolizumab and bevacizumab. Results: In the cirrhosis cohort, the low ferroptosis baseline in cirrhotic liver was significantly associated with higher liver cancer development. Among liver cancer cohorts, patients with the low ferroptosis baseline exhibited characteristics such as poor survival, increased hepatic stem cell features, and increased genomic instability. Notably, when liver cancer patients undergoing systemic treatment with sorafenib or the combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) were stratified using our genomic predictor, those with high ferroptosis baseline derived significant benefits from the combination of atezolizumab and bevacizumab treatment. Conversely, such benefit of treatment was not visible in patients treated with sorafenib. This suggests that ferroptosis activity may influence liver cancer response to immune checkpoint inhibitor therapy. Gene network analysis of the ferroptosis signature using ingenuity pathway analysis revealed that statin signatures are strongly correlated with high sensitivity to the combination treatment with of atezolizumab and bevacizumab, indicating that statins may be used for sensitizing liver cancer to the combination treatment. Conclusions: This study identifies clinically distinct subtypes of liver cancer associated with baseline ferroptosis, biomarkers associated with these subtypes, and potential mechanisms underlying ferroptosis-mediated sensitization of liver cancer cells to the combination of immunotherapy. This work emphasizes the potential of ferroptosis-targeted approaches in optimizing liver cancer treatment. Citation Format: Sowon Park, Hyewon Park, Yun Seong Jeong, Bo Hwa Sohn, Sun Young Yim, Sung Hwan Lee, Ju-Seog Lee. Ferroptosis as a determinant of prognosis and response to immunotherapy in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5349.