Disruption of FGL2 inducesTFEB-dependent lysosomal degradation of PD-L1 and enhances the efficacy of anti-PD1 therapy in hepatocellular carcinoma

Sep 22, 2026

Background: Binding of PD-L1 on cancer cells to PD-1 on T cells enables immune evasion. Despite approved anti-PD-1/PD-L1 therapies, limited responses and adaptive resistance require mechanism clarification. FGL2 promotes hepatocellular carcinoma via immunosuppressive processes, yet its regulation of the PD-1/PD-L1 axis and immunotherapy efficacy is unknown. Methods: Tumor tissues, GEPIA analyses, loss/gain-of-function, and mouse models tested FGL2 versus PD-1 blockade effects.

LanguageEnglish

CategoryResearch & Report

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Reading Time48 min

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Abstract

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Han et al. Cell Communication and Signaling (2026) 24:155 [https://doi.org/10.1186/s12964-026-02704-7](https://doi.org/10.1186/s12964-026-02704-7) Cell Communication and Signaling RESEARCH Open Access Disruption of FGL2 inducesTFEB- dependent lysosomal degradation of PD-L1 and enhances the efficacy of anti-PD1 therapy in hepatocellular carcinoma Meiwen Han1, Qianting Guan1, FangfeiYan1, Ming Wang1, Dong Xi1* and Qin Ning1* Abstract Background The ligation of programmed death ligand 1 (PD-L1) on cancer cells to programmed cell death-1 (PD1) expressed onT cells is a key mechanism of immune evasion. Despite the approval of anti-PD1/PD-L1 therapy for several cancers, the limited response rate and adaptive immune resistance emphasize the necessity to investigate the mechanisms regulating PD1/PD-L1 axis. Fibrinogen-like protein 2 (FGL2) advances hepatocellular carcinoma (HCC) development by triggering various immunosuppressive processes, but its role in modulating PD1/PD-L1 pathway and cancer immunotherapy is unknown. Methods Tumor tissue samples were utilized to explore the relationship between FGL2 expression and clinical prognosis in patients with HCC. The association between FGL2 and immune checkpoints was analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) platform. Loss-and gain-of-function experiments were employed to examine the influence of FGL2 on PD-L1 expression. The Hepa1-6 cell line was inoculated subcutaneously or orthotopically into wild-type (WT) and Fgl2 gene knockout (Fgl2-/-) mice, and combined interference with FGL2 inhibition and PD1 blockade was investigated. Results Patients with higher FGL2 expression had significantly poorer prognosis. A positive correlation was observed between FGL2 expression and immune checkpoints including PD1, PD-L1, cytotoxic T lymphocyte-associated protein 4 (CTLA4) and so on. In mouse models, knockout of FGL2 significantly suppressed tumor growth. Within the tumor microenvironment, PD-L1 expression on hepatoma cells and PD1, CTLA4 expression onT cells were significantly lower in Fgl2-/- mice than those in WT mice. Mechanistically, FGL2 regulated the phosphorylation and nuclear translocation of transcription factor (TF) EB through activating the mammalian target of rapamycin complex 1 (mTORC1) signaling, thereby inhibiting lysosome biosynthesis and PD-L1 degradation, which ultimately led to the upregulation of PD-L1 in hepatoma cells. FGL2 depletion synergized with PD1 blockade to maximize therapeutic outcomes. Histologically, *Correspondence: Dong Xi [xidong@tjh.tjmu.edu.cn](xidong@tjh.tjmu.edu.cn)[ ](xidong@tjh.tjmu.edu.cn)Qin Ning [qning@vip.sina.com](qning@vip.sina.com) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Han et al. Cell Communication and Signaling (2026) 24:155 Page 2

FAQs

What is the central immune-evasion mechanism investigated in this study?

The study focuses on how PD-L1 on tumor cells engages PD-1 on T cells to drive immune evasion, and why anti-PD-1 responses are often limited.

How was FGL2 linked to clinical outcomes in hepatocellular carcinoma?

Higher FGL2 expression in HCC patients was associated with significantly poorer prognosis, using analyses of tumor samples and expression datasets.

What molecular pathway explains the effect of disrupting FGL2 on PD-L1?

FGL2 activates mTORC1 signaling, promoting TFEB phosphorylation and nuclear translocation, which inhibits lysosome biosynthesis and PD-L1 degradation, leading to PD-L1 upregulation.

Sep 22, 2026

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