Tumors usually display fetal-like characteristics, and many
oncofetal proteins have been identified. However, fetal-like reprogramming of RNA splicing in
hepatocellular carcinoma (HCC) is poorly understood. Here, it is demonstrated that the expression of epithelial splicing regulatory
protein 2 (ESRP2), an RNA splicing factor, is suppressed in fetal hepatocytes and HCC, in parallel with
tumor progression. By combining
RNA-Seq with splicing analysis, it is identified that ESRP2 controls the fetal-to-adult switch of multiple splice
isoforms in HCC. Functionally, ESRP2 suppressed cell proliferation and migration by specifically switching the alternative splicing (AS) of the TAK1 gene and restraining the expression of the fetal and oncogenic
isoform, TAK1_ΔE12. Notably, aberrant TAK1 splicing led to the activation of p38MAPK signaling and predicted poor prognosis in HCC patients. Further investigation revealed that TAK1_ΔE12
protein interacted closely with TAB3 and formed liquid condensation in HCC cells, resulting in p38MAPK activation, enhanced cell migration, and accelerated
tumorigenesis. Loss of ESRP2 sensitized HCC cells to TAK1
kinase inhibitor (TAK1i), promoting pyroptotic cell death and CD8+ T cell infiltration. Combining TAK1i with immune checkpoint
therapy achieved potent
tumor regression in mice. Overall, the findings reveal a previously unexplored onco-fetal reprogramming of RNA splicing and provide novel therapeutic avenues for HCC.