CXCR4-Positive Antigen-Presenting Cancer-Associated Fibroblasts Identified by Spatial Transcriptomics as Immune Barriers in Hepatocellular Carcinoma Outstanding Award

BACKGROUND: Hepatocellular carcinoma (HCC) has a complex tumor microenvironment (TME) that influences tumor progression and immune responses. Cancer-associated fibroblasts (CAFs) are key stromal components, but their spatial distribution and role in immune modulation remain unclear. This study aimed to investigate the spatial organization of CAF subtypes and their impact on CD8+ T-cell infiltration in HCC.
METHODS: Spatial transcriptomics (Visium) was performed on seven HCC cases to identify CAF clusters. Immunohistochemical staining for aSMA, CD8, CD4, and CXCR4 was conducted on 96 HCC cases. Cell-cell interaction analysis using CellChat and prognostic analysis were performed to assess CAF-TIL interactions and clinical outcomes.
RESULTS: CAFs exhibited a consistent spatial distribution within tumor septa. Myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) were predominantly found on the tumor side, whereas antigen-presenting CAFs (apCAFs) localized to the non-tumor side. CXCR4 was identified as a specific marker of apCAFs, and its expression correlated with CD8+ T-cell exclusion. Notably, CD8+ T-cell infiltration was lower in tumor regions with high apCAF presence, suggesting a potential role of apCAFs in immune evasion. These findings indicate that CXCR4-positive apCAFs may serve as immune barriers in HCC.
CONCLUSIONS: CXCR4-positive apCAFs restrict CD8+ T-cell infiltration into tumors, contributing to immune exclusion. Targeting CXCR4 could enhance the efficacy of immune checkpoint inhibitors (ICIs) and offer a novel therapeutic approach for HCC.