KCTD1 stabilizes c-Myc to upregulate PD-L1 and suppress anti-tumor immunity in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the predominant histologic subtype of primary liver cancer and accounts for approximately 90% of cases worldwide. Although immune checkpoint blockade (ICB) therapies targeting the PD-1/PD-L1 axis have demonstrated clinical promise in advanced HCC, therapeutic responses remain heterogeneous, underscoring the need to elucidate the mechanisms governing PD-L1 expression. Here, we identify potassium channel tetramerization domain-containing protein 1 (KCTD1) as a previously unrecognized regulator of PD-L1 in HCC. Mechanistically, KCTD1 enhances PD-L1 expression through stabilizing of the oncoprotein c-Myc. Immunofluorescence and co-immunoprecipitation assays reveal a direct interaction between KCTD1 and c-Myc, mediated by the BTB domain of KCTD1 and the BR-HLH-LZ domain of c-Myc. Knockdown of KCTD1 leads to decreased c-Myc and PD-L1 protein levels, concomitant with increased production of pro-inflammatory cytokines, including IFN-γ and TNF-α, and augmented CD8⁺ T cell cytotoxic activity in vitro. In a murine intrahepatic tumor model, KCTD1 knockdown synergizes with anti-PD-1 therapy, resulting in enhanced tumor infiltration by CD4⁺ and CD8⁺ T lymphocytes and improved anti-tumor efficacy. These findings establish KCTD1 as a key modulator of immune evasion in HCC and a promising target to potentiate immune checkpoint therapy.