High expression of fibroblast activation protein in hepatocellular carcinoma: characteristics of angiogenesis and immune infiltration

Abstract Background The tumor microenvironment (TME) plays a critical role in the progression of hepatocellular carcinoma (HCC) and is associated with angiogenesis and antitumor immunity. Fibroblast activation protein (FAP) positive cancer-associated fibroblasts (CAFs) are important stromal components of the TME; however, their relationship with distinct vascular patterns, particularly vessels encapsulating tumor clusters (VETC) and tertiary lymphoid structures (TLS) remains poorly characterized. Materials and methods This multicenter study included a retrospective cohort of 1003 patients with HCC who underwent curative resection between January 2014 and June 2022 and a prospective genomic cohort of 23 patients enrolled between March 2024 and November 2025. FAP expression was evaluated using the H-score, and patients were classified into low- and high-FAP groups. Differences in microvascular density (MVD), VETC patterns, and TLSs were compared between the groups. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using log-rank tests before and after propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Single-cell RNA sequencing (scRNA-seq) was used to explore angiogenic and immune-related signatures. Results Compared to low-FAP HCCs (n = 777), high-FAP HCCs (n = 226) exhibited a significantly higher prevalence of poor tumor differentiation (51.3% vs. 30.8%), VETC patterns (44.2% vs. 28.2%), and elevated MVD levels (all adjusted P < 0.001), whereas the incidence of intratumoral TLSs was significantly lower (39.4% vs. 54.8%, adjusted P < 0.001). These associations remained significant after PSM and IPTW analyses. Patients in the low-FAP group had significantly better OS and RFS than those in the high-FAP group before matching (P < 0.001), after PSM (P = 0.041 for OS; P = 0.023 for RFS), and after IPTW (P = 0.030 for OS; P = 0.021 for RFS). scRNA-seq showed that high FAP expression was positively correlated with the proangiogenic marker PDGFRB (adjusted P < 0.001), and with angiogenesis-related signaling pathways, such as VEGF, MAPK, and focal adhesion. Furthermore, high FAP expression was associated with a reduced proportions of CD8 + tissue-resident memory T cells (TRM) (adjusted P = 0.044). Conclusions FAP expression is associated with a proangiogenic and immunosuppressive TME in HCC, characterized by the enrichment of VETC vascular patterns and reduced TLS formation. These findings suggest that FAP-positive CAFs may contribute to the spatial organization of tumor vasculature and immune exclusion, supporting further evaluation of FAP as a potential biomarker and therapeutic target in HCC.