Abstract
<title>Abstract</title> <p>Hepatocellular carcinoma (HCC) is one of the deadliest malignancies globally, characterised by a mean survival of 3 to 4 months upon late-stage diagnosis. While immunotherapy has shown success in managing HCC within specific patient subgroups, overall treatment response rates remain poor worldwide. In this study, we systematically investigated the role of long non-coding RNAs (lncRNAs) in a cohort of HCC patients treated with immunotherapy (nivolumab and ipilimumab) and surgical resection. Differentially expressed lncRNAs were identified using RNA-seq count data from 69 HCC tumor samples, and their functional roles were inferred via a guilt-by-association framework. Transcriptionally, lncRNAs were stage-specific and treatment-responsive. However, following immunotherapy, stage-specific differentially expressed genes (DEGs) were markedly attenuated in responders. Furthermore, we identified differentially expressed lncRNAs that were both stage-specific and stage-generic to immunotherapy. Finally, we used this collection of treatment-responsive lncRNAs from both stages to develop a panel of 12 robust lncRNA biomarkers that tracked immunotherapy progression. Overall, our findings capture stage- and treatment-specific lncRNA expression dynamics that could inform global disease monitoring and immunotherapy progression in HCC.</p>