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Background & Aims: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown., Methods: We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment., Results: We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1 + macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand‒receptor networks among malignant cells, SPP1 + macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1 + macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration., Conclusions: We identified that the TIB structure formed by the interaction of SPP1 + macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC., Impact and Implications: Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the role and prognostic value of mH2A1 in the progression of hepatocellular carcinoma (HCC)., Methods: Basing on the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and GEO datasets, the gene expression of mH2A1 and relative clinical characteristics were analyzed to assess the prognostic significant of mH2A1 in HCC. The protein expression of mH2A1 was measured by immunohistochemistry. Stable cell lines and nude mice model were used to investigate the role of mH2A1 in the progression of HCC., Results: In this study, using TCGA-LIHC data and HCC tissue microarray, we found that expression of mH2A1 was higher in tumor tissues than in adjacent normal tissues. These results were validated using the GEO database. Patients with high levels of mH2A1 were predicted to have larger tumor size and more advanced tumor stage and grade. Multivariate analysis revealed that increased mH2A1 expression was an independent prognostic risk factor of shorter overall survival (OS). Experimental results showed that elevated mH2A1 expression promoted the progression of HCC while reduced mH2A1 expression lead to opposite effects in vitro and in vivo. mH2A1 promoted the progression of HCC by regulating cell cycle via AKT. Dysregulated expression of mH2A1 was associated with its DNA methylation status. Two CpG sites (cg01466741 and cg02614129) were negatively correlated with mH2A1 expression. Notably, high methylation of both CpG sites was associated with better OS., Conclusion: Based on the above results, we concluded that upregulated mH2A1 in HCC promoted tumor progression and could serve as an unfavorable prognostic indicator., (Copyright © 2020. Published by Elsevier Inc.)