ArticleJHEP reports : innovation in hepatology2026
IL4I1+ macrophages drive hepatocellular carcinoma progression by responding to biomechanical cues.
Article in JHEP reports : innovation in hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND &
aimsThe tumor microenvironment undergoes dynamic biomechanical alterations during hepatocellular carcinoma (HCC) progression. However, the identification and characterization of biomechanically specialized macrophage subsets remains unexplored.
methodsIn 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.
resultsOur 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).
conclusionsOur study established that IL4I1 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.
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