Treatment of advanced liver cancer is still a major challenge in clinical settings because of its high heterogeneity, limited liver function reserve and narrow therapeutic window. In this article, the key challenges in the treatment of advanced liver cancer, including heavy disease burden, toxic accumulation of combined therapy and the balance dilemma between liver function protection and anti-tumor efficacy, were systematically reviewed. In this study, three optimization strategies were mainly illustrated: (1) Joint optimization of treatment modes. Synergistic sensitization mechanism and strategy of local and systemic therapy were investigated to explore the potential to enhance clinical efficacy for advanced liver cancer. (2) Functional protection of tumor treatment. Through dose optimization and course adjustment, the liver and systemic toxicities are minimized while ensuring clinical efficacy, thereby prolonging long-term survival. (3) Precise prediction of tumor treatment. Individualized therapy is achieved through biomarkers, molecular typing and artificial intelligence. The establishment of MDT under the framework of liver cancer center provides organizational guarantee for clinical translation of these strategies. In the future, it is necessary to further deepen the research of mechanism, optimize treatment strategies and spread successful experiences, eventually achieving the dual goals of prolonging survival time and improving the quality of life of patients with advanced liver cancer.