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Hepatocellular carcinoma (HCC) has an extremely poor prognosis. The emergence of immune checkpoint inhibitors (ICIs) has fundamentally transformed the therapeutic landscape for HCC. However, due to the limited response rate and complex resistance mechanisms of monotherapy, the core of clinical practice has shifted towards ICI-based combination strategies. This article systematically reviews the biological basis-primarily the immune microenvironment-and clinical evidence, including the limitations of monotherapy and the optimization of combination regimens, underlying this paradigm shift, as well as the challenges in achieving precision medicine (such as efficacy prediction and resistance). Finally, it points out that future breakthroughs rely on the integrated application of multi-omics-guided personalized regimens, engineered immune cell technologies, and AI-based predictive models. In summary, advancing HCC immunotherapy from broad combination strategies toward individualized precision combinations represents a promising direction for addressing current limitations and improving therapeutic benefit.