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

BACKGROUND: The ligation of programmed death ligand 1 (PD-L1) on cancer cells to programmed cell death-1 (PD1) expressed on T 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 on T 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, the combined interference group exhibited reduced expression of PD-L1, increased cytotoxicity of CD8(+) T cells, and decreased infiltration of Tregs within the tumors. CONCLUSION: In HCC, FGL2 promotes immune escape by inhibiting the lysosomal degradation of PD-L1 via mTOR-TFEB axis. Targeting FGL2 may serve as a potential therapeutic strategy to enhance the efficacy of anti-PD1 therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02704-7.