IL4I1+ macrophages drive hepatocellular carcinoma progression by responding to biomechanical cues

BACKGROUND & AIMS: The tumor microenvironment undergoes dynamic biomechanical alterations during hepatocellular carcinoma (HCC) progression. However, the identification and characterization of biomechanically specialized macrophage subsets remains unexplored. METHODS: In this study, single-cell RNA sequencing and spatial transcriptomics were used to characterized the spatial distribution patterns, phenotypic plasticity, and mechanoresponsive behaviors of IL4I1+ macrophages. Atomic force microscopy revealed substantial biomechanical heterogeneity within HCC tissues. Complementary in vitro and in vivo mechanobiology models demonstrated that macrophages dynamically respond to biomechanical cues and actively promote HCC progression. Furthermore, using a multimodal drug discovery platform combined with experimental validation, we elucidated IL4I1+ macrophages as a critical therapeutic target for HCC. RESULTS: Our findings demonstrate that IL4I1+ macrophages exhibit a distinct mechanosensitive phenotype capable of dynamically responding to biomechanical cues. Biomechanical-driven-IL4I1+ macrophages promote HCC progression by orchestrating multifaceted oncogenic programs, including enhanced tumor cell proliferation (n = 3, p <0.05), migratory capacity (n = 3, p <0.01), stem-like properties (n = 6, p <0.001), and immune evasion potential. SB505124 treatment significantly attenuated HCC progression in preclinical models, concomitant with a reduction in IL4I1+ macrophages (n = 5, p <0.001). CONCLUSIONS: macrophages respond to biomechanical cues within the tumor microenvironment and functionally convert them into immunosuppressive and pro-tumorigenic signals. These findings offer new insights into HCC mechanobiology and highlight IL4I1+ macrophage as a promising target for combination therapy. IMPACT AND IMPLICATIONS: The tumor microenvironment undergoes dynamic biomechanical changes in HCC progression. However, biomechanically responsive macrophage subsets remain poorly characterized. Here, we identify IL4I1+ macrophages as a biomechanics-sensing subpopulation that promotes HCC progression by fostering an immunosuppressive microenvironment and enhancing tumor proliferation, migration, and stemness. Our study unveils a novel mechanism by which macrophages regulate tumor progression from a biomechanical perspective and proposes a potential therapeutic strategy via targeted inhibition of IL4I1+ macrophages.