SOX12 Facilitates Hepatocellular Carcinoma Progression and Metastasis through Promoting Regulatory T‐Cells Infiltration and Immunosuppression

Abstract Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T‐cell (Treg) infiltration, decreases CD8 + T‐cell infiltration, and hastens HCC metastasis. Hepatocyte‐specific SOX12 knockout attenuates DEN/CCl 4 ‐induced HCC progression and metastasis, whereas hepatocyte‐specific SOX12 knock‐in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C‐C motif chemokine ligand 22 ( CCL22 ) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8 + T‐cell infiltration. Either knockdown of CCL22 or PD‐L1 dampens SOX12‐mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C‐021 or Treg‐specific knockout of CCR4 inhibits SOX12‐mediated HCC metastasis. Transforming growth factor‐β1 (TGF‐β1)/TGFβR1‐Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C‐021 or TGFβR1 inhibitor galunisertib with anti‐PD‐L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4‐Treg and PD‐L1‐CD8 + T axes. Blocking of CCR4 or TGFβR1 improves the efficacy of anti‐PD‐L1 in SOX12‐mediated HCC.