Immune Landscape and Differential Gene Expression in Hepatocellular Carcinoma: A Comparative Transcriptomic Analysis of Murine Models and Human TCGA Data

Abstract

Hepatocellular carcinoma (HCC) remains a major global health challenge, exhibiting poor prognosis and limited therapeutic options. Although programmed death receptor 1 (PD-1)-based immunotherapy can extend survival in some patients, its overall response rates in HCC are modest. To elucidate mechanisms underlying immunotherapy resistance, we studied transcriptomic data from RNA-seq analyses of two orthotopic murine HCC models—RIL-175 (responsive, “immunologically hot” tumor) and HCA-1 (resistant, “immunologically cold” tumor)—and 369 human HCC samples from The Cancer Genome Atlas (TCGA-LIHC). We used bulk RNA-seq deconvolution and differential gene expression analysis (DGEA) to examine how TP53 mutation influences immune infiltration and the potential effect of immune checkpoint blockade on the TME. Our findings reveal that only high-impact TP53 mutations aligned with reduced immune effector cell infiltration, implicating dysfunctional p53 in fostering an immunosuppressive microenvironment. Furthermore, our evaluation of differentially expressed genes highlighted E2F1 as a key factor enriched in the resistant HCA-1 model. Elevated E2F1 expression correlated negatively with cytotoxic T-cell presence in murine tumors and was associated with significantly poorer survival in TCGA-LIHC patients. These data suggest that reactivating p53 (e.g., via mRNA nanoparticle delivery) could synergize with PD-1 blockade, whereas E2F1’s central role in immunoevasion makes it a compelling therapeutic target. Collectively, this study underscores how careful mutation stratification and targeted immunomodulatory strategies hold promise for improving clinical outcomes in advanced HCC.