Liver cancer is the most frequent fatal malignancy globally and ranks fifth in the United States. The poor prognosis is largely due to late-stage diagnosis, with only 5% to 15% of patients eligible for surgical removal. Current treatment options, such as trans-arterial chemoembolization (TACE) and sorafenib, have limited efficacy and side effects. New approaches, including natural compounds, immunotherapy, and nanotechnology, show promise in improving outcomes. Natural compounds like piperine, curcumin, and oleocanthal have anti-tumor and anti-inflammatory properties, enhancing the efficacy of chemotherapeutics. Immunotherapy, particularly immune checkpoint inhibitors, targets cancer stem cells and enhances the immune system to fight cancer. Nanotechnology improves drug delivery, reducing toxicity and increasing selectivity, with applications in combination therapies. These advancements offer new hope for better patient outcomes and improved survival rates.Liver cancer is the most frequent fatal malignancy globally and ranks fifth in the United States. The poor prognosis is largely due to late-stage diagnosis, with only 5% to 15% of patients eligible for surgical removal. Current treatment options, such as trans-arterial chemoembolization (TACE) and sorafenib, have limited efficacy and side effects. New approaches, including natural compounds, immunotherapy, and nanotechnology, show promise in improving outcomes. Natural compounds like piperine, curcumin, and oleocanthal have anti-tumor and anti-inflammatory properties, enhancing the efficacy of chemotherapeutics. Immunotherapy, particularly immune checkpoint inhibitors, targets cancer stem cells and enhances the immune system to fight cancer. Nanotechnology improves drug delivery, reducing toxicity and increasing selectivity, with applications in combination therapies. These advancements offer new hope for better patient outcomes and improved survival rates.