Integrated multiomics analysis highlights the immunosuppressive role of granulin precursor positive macrophages in hepatocellular carcinoma.

It has been reported that tumor-associated macrophages (TAMs) play a complicated role in cancer occurrence and development, immune escape, and immune checkpoint blockade (ICB) resistance. However, the role of granulin precursor (GRN) highly expressed macrophages (hereafter refer to GRN(+) macrophages) in hepatocellular carcinoma (HCC) remains poorly understood. Herein, we systematically integrated multiomics analysis of human tumor tissues to illustrate the functional role of GRN(+) macrophages in HCC. GRN is selectively expressed by TAMs in different type of cancers including HCC, and was significantly associated with poor prognosis in several type of cancer. GRN was closely correlated with infiltration levels of most immune cells, especially the M2 macrophage cells in various cancers. In particular, both mRNA and protein expression level of GRN was significantly upregulated in HCC. Compared with tumor tissue, GRN was more significantly expressed in the stroma area between HCC tissues and adjacent non-tumor tissues. High expression of GRN was significantly correlated with M2-polarization of macrophages and T-cell exhaustion in HCC. GRN(+) macrophages communicated with intratumoral immune cells, especially CD8(+) T cells. Functionally, GRN(+) macrophages contacted with CD8(+) T cells, which inducing T-cell exhaustion. Our study offers a comprehensive understanding of the clinical relevance and immunological role of GRN(+) macrophages in HCC, indicating its potential role as a promising target for immunotherapeutic strategies.