Targeting different liver cancer hallmarks to boost immunotherapy response

Hepatocellular carcinoma (HCC) is a highly genetically heterogeneous malignancy with variable responses to immunotherapy. To improve therapeutic outcomes, it is essential to understand how different tumor-intrinsic features influence immune responses. In this study, we employ somatic genome-editing mouse models to establish a panel of murine HCC models with diverse genetic backgrounds. These models exhibit distinct immunological tumor profiles, allowing us to investigate the interplay between tumor genetics and immune evasion. We systematically analyze key cancer hallmarks—including metabolic phenotypes, genome instability, immune evasion, and other hallmark pathways—to elucidate their roles in shaping tumor immunogenicity. Our aim is to identify specific genetic and metabolic vulnerabilities that can be targeted to enhance immunotherapy responses. This research provides a comprehensive platform for understanding the mechanistic basis of immune resistance in HCC and may inform the development of personalized combinatorial treatment strategies to improve patient outcomes.