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Abstract Background Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, with a high mortality rate and poor prognosis. Mutated or dysregulated transcription factors (TFs) are significantly associated with carcinogenesis. The aim of this study was to develop a TF-related prognostic risk model to predict the prognosis and guide the treatment of HCC patients. Methods RNA sequencing data were obtained from the TCGA database. The ICGC and GEO databases were used as validation datasets. The consensus clustering algorithm was used to classify the molecular subtypes of TFs. Kaplan‒Meier survival analysis and receiver operating characteristic (ROC) analysis were applied to evaluate the prognostic value of the model. The immunogenic landscape differences of molecular subtypes were evaluated by the TIMER and xCell algorithms. Autodock analysis was used to predict possible binding sites of trametinib to TFs. RT‒PCR was used to verify the effect of trametinib on the expression of core TFs. Results According to the differential expression of TFs, HCC samples were divided into two clusters (C1 and C2). The survival time, signaling pathways, abundance of immune cell infiltration and responses to chemotherapy and immunotherapy were significantly different between C1 and C2. Nine TFs with potential prognostic value, including HMGB2, ESR1, HMGA1, MYBL2, TCF19, E2F1, FOXM1, CENPA and ZIC2, were identified by Cox regression analysis. HCC patients in the high-risk group had a poor prognosis compared with those in the low-risk group (p

Hepatocellular carcinoma (HCC) is a challenging malignancy with limited treatment options beyond surgery and chemotherapy. Recent advancements in targeted therapies and immunotherapy, including PD-1 and PD-L1 monoclonal antibodies, have shown promise, but their efficacy has not met expectations. Biomarker testing and personalized medicine based on genetic mutations and other biomarkers represent the future direction for HCC treatment. To address these challenges and opportunities, this comprehensive review discusses the progress made in targeted therapies and immunotherapies for HCC, focusing on dissecting the rationales, opportunities, and challenges for combining these modalities. The liver’s unique physiology and the presence of fibrosis in many HCC patients pose additional challenges to drug delivery and efficacy. Ongoing efforts in biomarker development and combination therapy design, especially in the context of immunotherapies, hold promise for improving outcomes in advanced HCC. Through exploring the advancements in biomarkers and targeted therapies, this review provides insights into the challenges and opportunities in the field and proposes strategies for rational combination therapy design.