Abstract
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.