TALDO1 promotes lipid metabolic reprogramming and immunosuppressive microenvironment remodelling in hepatocellular carcinoma

Abstract

Abstract Background Hepatocellular carcinoma (HCC) is characterized by pronounced metabolic reprogramming and is frequently accompanied by the development of an immunosuppressive microenvironment. However, the key molecular mediators linking tumour metabolic dysregulation to immune microenvironment remodelling remain insufficiently defined. This study aimed to identify critical metabolic genes in HCC and to investigate their roles in lipid metabolic reprogramming and immunosuppression. Methods A deep autoencoder was used to extract latent metabolic features from HCC and identify TALDO1 as a key candidate gene. The expression pattern and prognostic significance of TALDO1 were evaluated across multiple independent cohorts and further validated in clinical specimens. Multi‐omics analyses combined with experimental validation were then used to elucidate the role of TALDO1 in lipid metabolic reprogramming and its effects on immune microenvironment remodelling in HCC. Results TALDO1 was identified as a key metabolic gene associated with HCC progression and was consistently upregulated across multiple clinical cohorts. Mechanistically, TALDO1 promoted lipogenesis and lipid accumulation in HCC cells by suppressing AMPK activation and sustaining SREBP1 maturation. TALDO1 silencing also reduced the secretion of several fatty acids and lipid mediators. Multi‐omics analyses together with multiplex immunofluorescence validation showed that high TALDO1 expression was associated with an immunosuppressive microenvironment in HCC. Coculture experiments further demonstrated that TALDO1 silencing attenuated the ability of HCC cells to induce M2‐like macrophage polarization and promote phenotypes associated with T‐cell exhaustion. In vivo, TALDO1 loss was accompanied by reduced immunosuppressive cell infiltration, enhanced effector T‐cell activity, and impaired tumour growth. Consistently, TALDO1 silencing also markedly suppressed tumour growth in patient‐derived xenograft models. Conclusions TALDO1 promotes lipid metabolic reprogramming in HCC and participates in the formation of an immunosuppressive microenvironment. These findings suggest that TALDO1 may serve as a key molecule linking metabolic abnormalities to immune microenvironment remodelling and may have potential therapeutic significance. Key points TALDO1 promotes lipid metabolic reprogramming in HCC by regulating AMPK/SREBP1 signaling. TALDO1 is associated with the formation of an immunosuppressive tumour microenvironment. Multi‐omics analyses identified an association of TALDO1 with HCC progression and poor prognosis.