TNF-α Induces CCL28-Mediated Recruitment of Th22 Cells in Hepatocellular Carcinoma

Abstract Background The occurrence and development of hepatocellular carcinoma (HCC) are closely associated with the imbalance of the inflammatory and immune microenvironment. However, the regulatory mechanisms governing Th22 cell infiltration in HCC remain incompletely understood. This study aimed to investigate the molecular mechanism by which HCC cells recruit Th22 cells. Methods Peripheral blood mononuclear cells were isolated from healthy controls and newly diagnosed HCC patients, and subjected to flow cytometry, qPCR, Western blotting, chromatin immunoprecipitation, and Transwell migration assays. Results The results demonstrated that the proportion of naive CD4 ⁺ T cells in the peripheral blood of HCC patients was significantly lower than that in healthy controls, whereas the proportions of Th22 cells and CCL28 levels were markedly elevated. TNF-α induced the differentiation of naive CD4 ⁺ T cells into Th22 cells and upregulated the transcription and protein expression of CCR10 in HCC cells (HepG2) and T cells (Jurkat) in a concentration-dependent manner; this effect was independent of changes in CCR10 protein degradation rates. Mechanistically, TNF-α activated the NF-κB signaling pathway, promoting the nuclear translocation of the p65 subunit. Chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that activated p65 directly bound to specific sites within the CCR10 promoter region, thereby regulating its expression at the transcriptional level. Functional experiments revealed that HCC cells recruited CCR10-expressing Th22 cells via high CCL28 expression, an effect significantly inhibited by knocking down CCL28 or neutralizing CCR10. Conclusion This study is the first to elucidate the molecular mechanism by which the TNF-α/NF-κB/CCR10-CCL28 axis mediates the recruitment of Th22 cells by HCC cells. It reveals a positive feedback loop of "inflammatory cytokines–chemokines–immune cell recruitment" and provides a new theoretical basis for understanding the immune microenvironment in HCC, as well as potential novel targets for its diagnosis and targeted therapy.