Integrated multi-omics analyses reveal the TM4SF family genes with prognostic and therapeutic relevance in hepatocellular carcinoma.

TM4SF family members (TM4SFs) have been shown to be aberrantly expressed in multiple types of cancer. However, a comprehensive investigation of the TM4SFs has yet to be performed in LIHC. The study comprehensively investigated the expression and prognostic value of TM4SFs. Then, a TM4SFs-based risk model and nomogram were constructed for prognostic prediction. Finally, functional loss of TM4SFs was performed to verify the potential role of TM4SFs in LIHC. We found that TM4SFs were significantly up-regulated in LIHC. High expression and hypomethylation of TM4SFs were associated with poor prognosis of LIHC patients. Then, a TM4SFs-based risk model was constructed that could effectively classify LIHC patients into high and low-risk groups. In addition, we constructed a prognostic nomogram that could predict the long-term survival of LIHC patients. Based on immune infiltration analysis, high-risk patients had a relatively higher immune status than low-risk patients. Moreover, the prediction module could predict patient responses to immunotherapy and chemotherapy. Finally, loss-of-function studies showed that TM4SF4 knockdown could substantially suppress the growth, migratory, and invasive abilities of LIHC cells. Targeting TM4SFs will contribute to effective immunotherapy strategies and improve the prognosis of liver cancer patients.