Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide, with limited therapeutic options and a poor prognosis that continues to challenge clinicians and researchers alike. A groundbreaking study published in Genes & Immunity in 2025 casts new light on the molecular intricacies of HCC progression, specifically unraveling the pivotal role of the long non-coding RNA (lncRNA) known as TUG1. This research not only elucidates how TUG1 manipulates immune evasion mechanisms in HCC but also highlights its potential to augment the efficacy of the targeted drug lenvatinib, offering renewed hope for patients battling this aggressive cancer.
Long non-coding RNAs have emerged as master regulators in cancer biology, influencing gene expression without translating into proteins. Among these, TUG1 has garnered attention for its aberrant expression across various tumors. Despite initial indications of its involvement in HCC, the precise molecular pathways through which TUG1 exacerbates liver cancer remained elusive until the current investigation. The study leverages clinical data, bioinformatics, and state-of-the-art laboratory assays to map the oncogenic landscape sculpted by TUG1 in HCC.
The researchers first embarked on comprehensive expression analyses using RT-qPCR, supplemented by mining large-scale sequencing datasets from GEO and TCGA repositories. These analyses revealed a consistent and significant upregulation of TUG1 in HCC tissues compared to healthy liver counterparts, with the highest expression levels correlating with more advanced clinical stages. Notably, this upregulation of TUG1 tightly paralleled the increased expression of programmed death-ligand 1 (PD-L1), a well-documented immune checkpoint protein notorious for enabling tumor cells to escape immune surveillance.
The connection between TUG1 and PD-L1 emerged as a compelling axis in HCC immunobiology. PD-L1’s role in dampening the host immune response, particularly by impairing CD8+ cytotoxic T lymphocytes, is a cornerstone of tumor immune evasion. By demonstrating a positive correlation between TUG1 levels and PD-L1 expression, the study proposed that TUG1 may be a key upstream regulator of immune checkpoint dynamics in liver cancer.
Functionally, the team conducted a series of in vitro assays to interrogate the impact of TUG1 on HCC cell behavior and immune interactions. These included the Cell Counting Kit-8 (CCK8) for measuring proliferation, colony formation assays to assess clonogenic potential, and transwell assays to evaluate invasive capacity. Elevated TUG1 expression consistently augmented these oncogenic traits, fostering more aggressive cellular phenotypes. Conversely, silencing TUG1 drastically curtailed proliferation and invasion, underscoring its role as a facilitator of tumor growth.
Immunologically, the researchers performed co-culture experiments between HCC cells and CD8+ T cells to assess cytotoxic efficacy. Strikingly, HCC cells with reduced TUG1 expression became more susceptible to CD8+ T cell-mediated killing, an effect that aligned with decreased PD-L1 levels. This finding illuminated TUG1 as a molecular shield protecting cancer cells from immune attack, directly linking its expression to compromised antitumor immunity.
The study further investigated how TUG1 exerts its regulatory influence on PD-L1. Using dual-luciferase reporter assays, the team demonstrated that TUG1 acts as a competitive endogenous RNA (ceRNA), or “sponge,” for microRNA miR-377-3p. Under normal conditions, miR-377-3p binds to the 3′ untranslated region of PD-L1 mRNA, restricting its translation. However, TUG1 sequesters miR-377-3p, freeing PD-L1 mRNA from repression and enabling its overexpression. This molecular interplay delineates a finely tuned post-transcriptional control mechanism promoting immune evasion.
An immensely significant aspect of the study involves lenvatinib (LEN), a tyrosine kinase inhibitor approved for advanced HCC treatment. While LEN displays notable antitumor activity, resistance often emerges, fueled by complex molecular circuits. The researchers found that LEN treatment of HCC cells substantially suppressed both TUG1 and PD-L1 expression, thereby enhancing CD8+ T cell-mediated cytotoxicity against tumor cells. This observation proposed that LEN not only disrupts oncogenic signaling but also revitalizes antitumor immune responses by downregulating key immune checkpoint modulators.
Critically, the overexpression of TUG1 in HCC cells diminished LEN’s cytotoxic impact, effectively dampening the drug’s therapeutic potential. In contrast, targeted knockdown of TUG1 synergized with LEN treatment, producing a remarkable decrease in tumor cell viability and improved immune-mediated clearance. These findings unfold the possibility that TUG1 expression status could serve as a predictive biomarker for LEN responsiveness while positioning TUG1 as an adjuvant therapeutic target.
To translate these insights beyond the petri dish, the authors conducted in vivo experiments using xenograft mouse models of HCC. The combination of TUG1 knockdown and LEN administration significantly retarded tumor growth compared to either treatment alone. Correspondingly, tumor specimens from treated animals exhibited heavily reduced PD-L1 expression and increased infiltration of cytotoxic CD8+ T cells, confirming the in vitro mechanistic model. This powerful preclinical evidence strengthens the rationale for targeting TUG1 to enhance existing therapies.
Beyond illuminating the molecular dance between TUG1, miR-377-3p, and PD-L1, this research sets the stage for novel interventional strategies in HCC. Targeted silencing of TUG1 could disrupt tumor immune escape, revitalizing endogenous anticancer immunity while boosting the efficacy of frontline drugs like lenvatinib. Such dual benefits could address the pressing problem of therapeutic resistance and improve patient survival outcomes.
The implications of these findings extend beyond hepatocellular carcinoma alone, as similar lncRNA-mediated immune regulatory pathways might operate in other solid tumors. The paradigm of lncRNA sponge activity modulating checkpoint proteins presents fertile ground for future oncology research and drug development. Harnessing intricacies of RNA-mediated gene expression control could revolutionize immunotherapy approaches.
This study also accentuates the importance of integrating transcriptomic data with functional immunology to unravel the complex regulatory networks underpinning cancer progression. By combining high-throughput bioinformatics analyses and rigorous laboratory validations, the team exemplifies contemporary translational cancer research that can bridge bench-to-bedside gaps.
In conclusion, the discovery that TUG1 fosters HCC progression through miR-377-3p sponging and subsequent PD-L1 upregulation not only enriches our molecular understanding of liver cancer but opens new avenues for therapeutic intervention. Targeting TUG1 emerges as a promising strategy to potentiate cancer immunosurveillance and enhance the clinical utility of lenvatinib, potentially transforming the treatment landscape for this devastating disease.
As global oncology shifts toward precision medicine, such insights underscore the necessity of exploring lncRNAs as both biomarkers and drug targets. Continued investigation into TUG1 and its regulatory networks will be crucial to developing next-generation therapeutics that more effectively combat hepatocellular carcinoma and possibly other malignancies resistant to conventional treatment.
Subject of Research: Hepatocellular carcinoma, long non-coding RNA TUG1, PD-L1 immune checkpoint, miR-377-3p interaction, lenvatinib efficacy
Article Title: TUG1 targeting enhances anticancer immunity thereby facilitating lenvatinib efficacy in hepatocellular carcinoma
Article References:
Che, S., He, L., Chen, Q. et al. TUG1 targeting enhances anticancer immunity thereby facilitating lenvatinib efficacy in hepatocellular carcinoma. Genes Immun (2025). https://doi.org/10.1038/s41435-025-00358-y
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41435-025-00358-y
Keywords: Hepatocellular carcinoma, long non-coding RNA, TUG1, PD-L1, immune evasion, miR-377-3p, lenvatinib, cancer immunotherapy, RNA sponging, tumor microenvironment
