Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide.Although immunotherapy provides hope for advanced HCC patients, the outcomes are not satisfactory and vary by individual case. In this study, we sought to establish novel molecular subtypes and a stable model based on tumor-related pathways for guiding the immunotherapy in HCC patients.Methods: A total of 15 pathways including immune pathways, stromal pathways, oncogenic pathways, and DNA damage repair pathways were used to construct molecular subtypes through consensus clustering.Immune characteristics, gene mutations, and genomic alterations including copy number variations and homologous recombination deficiency (HRD) were analyzed in different clusters. The Tumor Immune Dysfunction and Exclusion (TIDE) framework was used to predict the response to immunotherapy.Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression were employed to screen prognostic genes for constructing a risk model.Results: Three clusters/subtypes were constructed including Immune-E, Immune-D and Stromal-E.Immune-D had the worst prognosis and high enrichment of HRD pathways. Immune-E had higher immune infiltration, higher expression of major histocompatibility complex (MHC)-related genes, and higher expression of PD1, PDL1, CTLA4, and LAG3. TP53 alterations frequently occurred in Immune-D.Immune-E had a relatively high response to immunotherapy and was sensitive to chemotherapeutic drugs. Moreover, we constructed an IMScore model that was effective to classify HCC patients into different risk groups, and the IMScore had a better performance than the TIDE score.Conclusions: This study revealed the complex interaction among the tumor microenvironment (TME), genomic alterations, and tumor-related pathways by exploring the molecular difference of 3 subtypes. The IMScore model has potential to provide guidance for immunotherapy in HCC patients.