ObjectiveTo summarize the clinical characteristics, potential molecular mechanisms, and predictive biomarkers of hyperprogressive disease (HPD) associated with the treatment of hepatocellular carcinoma (HCC) with immune checkpoint inhibitors and to explore its clinical implications. MethodsThe relevant domestic and international literature was reviewed to analyze the definition, mechanisms, and predictive factors of HPD. Particular attention was given to key factors affecting HPD development, including clinical characteristics, tumor microenvironment, genetic mutations, and inflammatory factors. ResultsHPD significantly decreased the survival of HCC patients. Its occurrence might be associated with individual variability, dysregulation of the tumor microenvironment, tumor-related genetic mutations, and elevated level of inflammatory factors. Clinical features such as female, advanced age, elevated Child-Pugh score, portal vein tumor thrombus could identify high-risk populations for HPD. Blood-based biomarkers such as neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and alpha-fetoprotein showed potential value in predicting HPD. ConclusionsSystematic investigation of the molecular mechanisms and predictive biomarkers of HPD are crucial for optimizing immunotherapy strategies and improving patient’s outcomes. Large-scale, multi-center studies are needed to achieve precise prediction and personalized intervention in the future.