M2 macrophages play a crucial role in promoting tumor angiogenesis and proliferation, as well as contributing to chemotherapy resistance and metastasis. However, their specific role in the tumor progression of hepatocellular carcinoma (HCC) and their impact on the clinical prognosis remain to be further elucidated.M2 macrophage-related genes were screened using CIBERSORT and weighted gene co-expression network analysis (WGCNA), while subtype identification was performed using unsupervised clustering. Prognostic models were constructed using univariate analysis/least absolute shrinkage selector operator (LASSO) Cox regression. In addition, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and mutation analysis were used for further analysis. The relationship between the risk score and tumor mutation burden (TMB), microsatellite instability (MSI), the efficacy of transcatheter arterial chemoembolization (TACE), immunotype, and the molecular subtypes were also investigated. Moreover, the potential role of the risk score was explored using the ESTIMATE and TIDE (tumor immune dysfunction and exclusion) algorithms and stemness indices, such as the mRNA expression-based stemness index (mRNAsi) and the DNA methylation-based index (mDNAsi). In addition, the R package "pRRophetic" was used to examine the correlation between the risk score and the chemotherapeutic response. Finally, the role of TMCC1 in HepG2 cells was investigated using various techniques, including Western blotting, RT-PCR and Transwell and wound healing assays.This study identified 158 M2 macrophage-related genes enriched in small molecule catabolic processes and fatty acid metabolic processes in HCC. Two M2 macrophage-related subtypes were found and a four-gene prognostic model was developed, revealing a positive correlation between the risk score and advanced stage/grade. The high-risk group exhibited higher proliferation and invasion capacity, MSI, and degree of stemness. The risk score was identified as a promising prognostic marker for TACE response, and the high-risk subgroup showed higher sensitivity to chemotherapeutic drugs (e.g., sorafenib, doxorubicin, cisplatin, and mitomycin) and immune checkpoint inhibitor (ICI) treatments. The expression levels of four genes related to the macrophage-related risk score were investigated, with SLC2A2 and ECM2 showing low expression and SLC16A11 and TMCC1 exhibiting high expression in HCC. In vitro experiments showed that TMCC1 may enhance the migration ability of HepG2 cells by activating the Wnt signaling pathway.We identified 158 HCC-related M2 macrophage genes and constructed an M2 macrophage-related prognostic model. This study advances the understanding of the role of M2 macrophages in HCC and proposes new prognostic markers and therapeutic targets.Copyright © 2023 Song, Wang, Zhang and He.