Abstract
Immunotherapy targeting tumor-associated macrophages (TAMs) is a promising approach to treating cancer. However, the limited drug targets and ambiguous mechanisms impede the development of clinical immunotherapy strategies. To elucidate the underlying processes involved in mononuclear phagocyte (MNP) infiltration and phenotypic changes in hepatocellular carcinoma (HCC), we integrated single-cell RNA-sequencing data from 100,030 cells derived from patients with HCC and healthy individuals and compared the phenotypes and origins of the MNPs in the tumor core, tumor periphery, adjacent normal tissue, and healthy liver samples. Using machine learning and multi-omics analyses, we identified 445 infiltration-associated genes and potential drug targets affecting this process. Through in vitro experiments, we found that the expression of macrophage migration inhibitory factor (MIF) is the upstream regulator of secreted phosphoprotein 1 (SPP1) and promote migration in TAMs. Our findings also indicate that MIF promotes tumor metastasis and invasion and is a promising potential target for treating HCC.