(1) Background: It is well-known that long non-coding RNAs (lncRNAs) and N7-methylguanosine (m7G) contribute to hepatocellular carcinoma (HCC) progression. However, it remains unclear whether lncRNAs regulating m7G modification could predict HCC prognosis. Thus, we sought to explore the prognostic implications of m7G-related lncRNAs in HCC patients. (2) Methods: Prognostic M7G-related lncRNAs obtained from The Cancer Genome Atlas (TCGA) database were screened by co-expression analysis and univariate Cox regression analysis. Next, the m7G-related lncRNA signature (m7GRLSig) was conducted by Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analysis. Kaplan–Meier analysis and time-dependent receiver operating characteristics (ROC) assessed the prognostic abilities of our signature. Univariate and multivariate Cox regression, nomogram, and principal component analysis (PCA) were conducted to evaluate our signature. Subsequently, we investigated the role of m7GRLSig on the immune landscape and sensitivity to drugs in HCC patients. The potential function of lncRNAs obtained from the prognostic signature was explored by in vitro experiments. (3) Results: A novel m7GRLSig was identified using seven meaningful lncRNA (ZFPM2-AS1, AC092171.2, PIK3CD-AS2, NRAV, CASC19, HPN-AS1, AC022613.1). The m7GLPSig exhibited worse survival in the high-risk group and served as an independent prognostic factor. The m7GRLSig stratification was sensitive in assessing the immune landscape and sensitivity to drugs between the high-risk and low-risk groups. Finally, in vitro experiments confirmed that the knockdown of NRAV was accompanied by the downregulation of METTL1 during HCC progression. (4) Conclusions: The m7G-related signature is a potential predictor of HCC prognosis and contributes to individualize the effective drug treatment of HCC.

Adoptive T cell therapy for advanced hepatocellular carcinoma (HCC) is limited by the immunosuppressive tumor microenvironment, which impairs T-cell function. Overcoming this immunosuppression and restoring T-cell functionality are crucial for improving therapeutic efficacy. Here, we investigated the role of taurine in regulating alpha-fetoprotein (AFP)-specific T-cell receptor-engineered T cells (TCR-T) function. Metabolomic profiling revealed that intracellular taurine levels declined during the early phase of T-cell activation, while expression of the taurine transporter SLC6A6 increased over time. In addition, taurine abundance was lower in HCC tissues than in normal liver tissues in vivo, suggesting that taurine availability is reduced during both T-cell activation and tumor progression. Functionally, taurine supplementation enhanced the cytotoxic activity, persistence, and intratumoral infiltration of AFP-specific TCR-T, while reducing exhaustion and apoptosis after repetitive tumor stimulation. In contrast, taurine-limited conditions impaired T-cell proliferation and survival, attenuated antitumor activity in vitro and in vivo, and promoted an exhaustion-prone phenotype. Taurine supplementation also partially restored the function of β-alanine-preconditioned T cells. Mechanistically, transcriptomic and proteomic analyses identified PI3K-AKT signaling as a key pathway associated with taurine-mediated T-cell regulation. Taurine-limited T cells showed reduced AKT phosphorylation and developed a metabolically stressed state characterized by increased mitochondrial respiration, glycolytic activity, reactive oxygen species production and mitochondrial structural abnormalities during activation. Together, these findings identify taurine availability as an important metabolic regulator of engineered T-cell fitness and support taurine-based metabolic conditioning as a potential strategy to improve TCR-T therapy for HCC.