Tumor Immune Microenvironment Analysis of the Stemness-High Subtype in Resectable Hepatocellular Carcinoma

Background/Objectives: Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy comprising distinct molecular subtypes with variable clinical behavior. Among them, the stemness-high (STM) subtype is characterized by elevated cancer stemness signatures, poor prognosis, and limited treatment responsiveness. This study aimed to comprehensively characterize the tumor microenvironment (TME) of the STM subtype in resectable HCC. Methods: Transcriptomic data from four independent HCC cohorts (Korea, Samsung, Zhongshan, and Modena) and the TCGA-LIHC cohort were analyzed. Survival outcomes and clinicopathologic features were compared between STM and other subtypes, and multivariable Cox regression was used to adjust for clinical covariates. TME composition was estimated with multiple deconvolution algorithms implemented in TIMER3 (CIBERSORT, CIBERSORT-ABS, MCP-counter, EPIC, quanTIseq, and ConsensusTME), and cell states were defined using EcoTyper. Tumor Immune Dysfunction and Exclusion (TIDE) analysis was used to assess immune dysfunction, immune exclusion, and predicted response to immune checkpoint inhibitors (ICIs). Overall survival under atezolizumab plus bevacizumab was examined in the IMbrave150 cohort. Results: The STM subtype was associated with worse survival, higher T stage, and poor differentiation, with a non-significant trend toward more frequent vascular invasion. After adjustment, it remained associated with shorter overall survival (pooled HR 2.13, 95% CI 1.42–3.19). Immune analyses revealed enrichment of cancer-associated fibroblasts, regulatory T cells, myeloid-derived suppressor cells, pro-migratory-like fibroblasts, exhausted/effector memory/Treg-like CD4+ T cells, and tumor-associated endothelial cells. STM tumors displayed higher TIDE, exclusion, dysfunction, PD-L1, and Merck18 scores, indicating an immunosuppressive TME. In patients treated with atezolizumab plus bevacizumab, the STM subtype was also associated with shorter overall survival. Conclusions: This study provides insights into the immunologic landscape of the STM subtype of HCC. Given its immune evasion features and poor prognosis even under ICI-based treatment, stemness-high HCC may require alternative precision therapeutic strategies.