Prognostic impact of tertiary lymphoid structures and cancer-associated fibroblasts in hepatocellular carcinoma with portal vein tumor thrombus

The significance of tertiary lymphoid structures (TLS) in hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains ambiguous. This study evaluates the prognostic impact of intra-tumoral TLS (iTLS) and peri-tumoral TLS (pTLS) and explores the interplay between TLS and cancer-associated fibroblasts (CAF) in patients undergoing curative hepatic resection. A retrospective analysis of 83 HCC patients with PVTT assessed the prognostic value of TLS. Transcriptomic data were mined to identify TLS- and CAF-related genes, and a seven-gene prognostic model was constructed using LASSO and Cox regression analyses. Immune microenvironment, mutation characteristics, and response to immunotherapy were analyzed between risk groups. iTLS + and high pTLS density were independently associated with improved overall survival (OS), but not recurrence-free survival (RFS) or early recurrence. A novel risk model comprising KLF2, HBEGF, KLRB1, PGF, JAM2, CHORDC1, and YTHDF2 stratified patients into high- and low-risk groups, with the high-risk group demonstrating poorer OS and diminished immunotherapy responsiveness. Low-risk patients exhibited higher immune infiltration (e.g., B cells, T cells) and stronger antitumor activity, whereas high-risk tumors showed active proliferation and immune evasion. iTLS and pTLS are independent predictors of favorable OS in HCC patients with PVTT. The TLS/CAF-based risk model offers robust prognostic utility and highlights distinct biological and immune features between patient subgroups. These findings provide a foundation for personalized prognostic assessment and therapeutic decision-making in advanced HCC.