ArticleTranslational cancer research2025
APOA2 mediates immune therapy tolerance in hepatocellular carcinoma by inhibiting the antigen-presenting function of dendritic cells through the PPAR signaling pathway.
Article in Translational cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Combinatorial treatment with donafenib and quercetin suppresses lipid metabolism in HepG2 cells by targeting the CREB1/DRP1/SREBP1 axis.Translational cancer research · 2026Article
- Neoepitopes at the crossroads of immunometabolism: metabolic remodeling of antigen presentation in type 1 diabetes.Frontiers in immunology · 2026Review
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11 authors.
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Abstract
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, characterized by high heterogeneity and poor prognosis. Despite advances in systemic therapies, including immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), treatment efficacy remains limited. This study investigated the mechanisms underlying resistance to combined targeted therapy and immunotherapy in HCC. Methods: We integrated spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) data from cabozantinib-nivolumab-treated patients, using the RCTD algorithm for cell-type deconvolution. High-dimensional weighted gene co-expression network analysis (hdWGCNA) identified resistance-associated modules, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and correlation analyses to characterize APOA2/SPINK1 roles in the tumor microenvironment (TME). Spatial niches were defined via the Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA) algorithm based on cell-type co-occurrence patterns, and multiscale co-localization was analyzed using the Multiview Intercellular SpaTial modeling framework (Misty). Ligand-receptor interactions were validated by CellChat, with results confirmed using The Cancer Genome Atlas (TCGA) bulk RNA-sequencing data. Results: Thirty-nine resistance-associated genes were identified, with APOA2 and SPINK1 emerging as pivotal hub genes. APOA2 mediated immune resistance by impairing dendritic cell (DC) antigen presentation through the PPAR signaling pathway, contributing to a suppressive TME. SPINK1 was associated with tumor aggressiveness, enhancing invasion, metastasis, and therapy tolerance. Lipid metabolism pathways were enriched in the non-responder (NR) group, underscoring the role of metabolic reprogramming in immune evasion and treatment resistance. Correlation analyses revealed that APOA2 expression was negatively associated with major histocompatibility complex (MHC) molecule expression. Conclusions: This study highlights the critical roles of APOA2, SPINK1, and lipid metabolism in shaping an immunosuppressive TME and driving treatment resistance in HCC. These findings provide novel insights into the mechanisms of resistance and offer a foundation for developing therapeutic strategies for better clinical outcomes.
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