Aggressive features and immune landscape of macrotrabecular hepatocellular carcinoma

This study aimed to investigate the clinical, pathological, and immune characteristics of macrotrabecular hepatocellular carcinoma (MT-HCC) to identify distinct features, evaluate prognostic significance, and explore potential therapeutic targets for MT-HCC. A total of 83 MT-HCC and 111 CV-HCC patients who underwent liver resection were included. Clinicopathological data were analyzed using statistical methods. Among these cases, immunohistochemical (IHC) staining was performed on 48 cases of massive trabecular hepatocellular carcinoma to evaluate the distribution of immune cells across different tumor regions. The Friedman test, Spearman's correlation analysis, Kaplan-Meier survival analysis, and Cox regression analysis were used to examine the relationships between immune infiltration characteristics and prognosis. MT-HCC exhibited more aggressive features, such as higher serum AFP levels (68% vs. 21%, p < 0.001), larger tumor size (7.65 cm vs. 4.47 cm, p < 0.001), and a higher frequency of vascular invasion (22% vs. 4%, p < 0.001), satellite nodules (41%vs. 16%, p < 0.001), and tumor necrosis (84% vs. 47%, p < 0.001). Survival analysis showed worse overall survival and higher recurrence rates in MT-HCC. The immune microenvironment displayed a typical "immune desert" phenotype, characterized by the spatial distribution of adaptive immune cells: sparse distribution within the tumor, enrichment at tumor margins, and enrichment adjacent to the tumor. In MT‑HCC, PD‑L1 expression was extremely low across all three tumor regions, whereas CTLA‑4 showed specific high expression at the tumor margins. Intratumoral CD8⁺ T cells exhibited a significant positive correlation with PD‑1 and CTLA‑4 (r = 0.701, P < 0.001), suggesting the dual exhaustion state of intratumoral T cells. Multivariate analysis identified cross‑regional FOXP3⁺ Treg infiltration, maximum tumor diameter, and macrovascular invasion as independent risk factors for overall survival. Conversely, peritumoral CD4⁺ T cells served as protective immune markers and were associated with reduced mortality risk in patients. The findings suggest that MT-HCC possesses invasive clinical characteristics and exhibits distinctive spatial immune heterogeneity, where immune cell distribution plays a critical role in prognosis. Targeting specific immune cell populations may offer new therapeutic strategies for MT-HCC and improve patient outcomes.