Crosstalk between TFF2+ HCC cells and regulatory T cells drives hepatocellular carcinoma prometastatic niche formation and portal vein tumor thrombosis

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Background Portal vein tumor thrombosis (PVTT) is a critical event that promotes intrahepatic dissemination, induces portal hypertension, and worsens the prognosis of hepatocellular carcinoma (HCC), yet its formation mechanism remains poorly understood. Methods TFF2 + HCC cells were identified in hepatocellular carcinoma by analyzing 15 single-cell RNA sequencing samples from 5 HCC patients with PVTT. The stemness and invasive characteristics of these cells were then assessed via bioinformatic analysis of public HCC cohorts and experimental validation. Spatial transcriptomic analysis of 15 HCC samples revealed the cellular interactions between TFF2 + HCC cells and the tumor microenvironment, findings that were further corroborated by gene co-expression analysis, cellular co-localization analysis, and immunohistochemistry. Finally, the translational potential of targeting TFF2 was evaluated through in vivo gene knockdown experiments. Results We identified TFF2 + HCC cells with stemness traits, high metastatic potential, and altered TKI response, which were enriched in HCC and PVTT tissues and associated with poor prognosis. ATF4 was identified as a specific regulator maintaining stemness and promoting EMT in TFF2 + HCC cells. Multi-omics analysis revealed that TFF2 + HCC cells recruit regulatory T cells (Tregs) into the TME and activate their immunosuppressive function via the TFF2-CXCR4 interaction. These Tregs, in turn, activate an ATF4-dependent pro-metastatic signaling cascade in TFF2 + HCC cells via TGFB1-TGFBR1 interaction, establishing a reciprocal tumor-promoting loop. In vivo models confirmed that TFF2 inhibition suppresses Tregs recruitment and attenuates HCC metastasis. Conclusion In summary, our study highlights TFF2 + HCC cells as a driver of invasive HCC with PVTT, proposing potential therapeutic targets and insights.

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