RECENT ADVANCES IN IMMUNOTHERAPY AND TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA (HCC): MOLECULAR MECHANISMS, CLINICAL PROGRESS, AND FUTURE DIRECTIONS

Abstract

Hepatocellular carcinoma (HCC) is an extremely dangerous cancer globally with high molecular heterogeneity, late diagnosis, and treatment inefficacy. Knowingly, the last 10 years have brought about the immunotherapy and targeted therapies that have transformed the way advanced HCC is treated to be replaced with the traditional monotherapy therapy, based on sorafenib. IMbrave150, CheckMate 040, and HIMALAYA deliver valuable results to the domain of immune checkpoint inhibitors (ICIs) and their combinations with anti-angiogenic agents, becoming a new standard of care, with a significant positive impact on overall survival and the quality of life. Simultaneously, the identification of molecular drivers and the explanation of the signaling effectors oncogenic as the Wnt/ 2 -catenin, PI3K/Akt/mTOR, and MAPK have informed resistance mechanisms and facilitated the advances of precision therapies. Irrespective of these developments, therapeutic resistance, immune evasion and toxicities associated with treatment are significant problems. The current studies focus on the combination of theliquid biopsy, circulating tumor DNA (ctDNA), and multi-omics platforms to determine predictive biomarkers and maximize patient stratification. Also, clinical efficacy and practical applicability are convergent at the point of real-world evidence and adaptive designs of clinical trials, so that precision immuno-oncology is a reality. Future perspectives are on coupled ICIs with epigenetic modulators, metabolic inhibitors, and adoptive cell therapies that can lead to long-term responses and worldwide efforts, which can bolster access and equity in the treatment of HCC. This is an overarching review of the current literature that outlines the molecular pathways, treatment advances, and translation issues that are changing the management of HCC in the context of targeted and immune-based treatment.