Abstract Hepatocellular carcinoma (HCC) incidence and mortality continue to rise in the United States, largely driven by increasing rates of chronic liver disease, viral hepatitis, and metabolic dysfunction. Despite progress in immunotherapy, first-line immune checkpoint inhibitor (ICI)-based combinations benefit only a subset of patients, and many individuals with HCC are ineligible due to contraindications such as varices, autoimmune disorders, or immunosuppression. Second-line agents, including the multi-kinase inhibitor lenvatinib, provide only modest and short-lived clinical responses. These persistent challenges—tumor heterogeneity, rapid development of therapeutic resistance, and limited options for patients with hepatic dysfunction—underscore the urgent need for innovative, durable, and widely accessible treatment strategies for HCC. Epigenetic dysregulation mediated by the histone demethylase LSD1 (KDM1A) is a key driver of HCC stemness, plasticity, and immune evasion. LSD1 is frequently overexpressed in HCC and strongly associated with poor survival. Notably, high LSD1 expression correlates with adverse clinical outcomes in both CD8+ T cell-enriched and CD8+ T cell-exhausted tumors, highlighting its role in establishing a cold or immunosuppressed tumor microenvironment. Thus, we hypothesize that LSD1 inhibition will suppress aggressive tumor phenotypes, limit intratumoral heterogeneity, delay therapeutic resistance, and enhance anti-tumor immunity, with enhanced efficacy when combined with lenvatinib. Our preliminary data support this hypothesis. Pharmacologic inhibition or genetic depletion of LSD1 with or without Lenvatinib treatment significantly reduces HCC cell proliferation and aggressive tumor behaviors—including migration, invasion, tumor sphere formation, and xenograft tumor growth. Importantly, the combination of LSD1 inhibition and lenvatinib further enhances CD8+ T cell-mediated immune surveillance and restores immune killing capacity against HepG2 cells, which are typically resistant to immune-mediated cytotoxicity. These findings provide a strong mechanistic and translational rationale for advancing LSD1-targeted epigenetic therapy, alone or in combination with lenvatinib, as a promising therapeutic strategy for patients with advanced HCC who are underserved by current ICI-based treatments. By directly targeting LSD1-driven epigenetic reprogramming and overcoming key resistance mechanisms, this project addresses a critical unmet medical need and establishes a robust foundation for future clinical evaluation of combined LSD1-Lenvatinib therapy. Citation Format: Kyounghyun Kim, HongDuck Yun, Gabin Kwon. Dual epigenetic-kinase targeting to overcome resistance and immune evasion in hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1276.
KIm et al. (2026) studied this question.