Abstract

Bladder cancer progression is frequently accompanied by metabolic reprogramming and immune escape, yet how these processes are coupled remains unclear. Sterol regulatory element-binding transcription factor 1 (SREBF1) governs lipid homeostasis and is often deregulated in cancer. We find that SREBF1 is upregulated in human bladder tumours and associates with invasion, metastasis and poor patient outcome, critically, it sustains tumor growth by driving immune evasion. Mechanistically, SREBF1 directly interacts with the SUMO E3 ligase TRIM28, which catalyses SUMO2 conjugation of SREBF1 at K470, antagonizes K48-linked ubiquitination and stabilizes SREBF1. TRIM28 further enhances SREBF1 occupancy at the MGAT4A promoter and upregulates MGAT4A, thereby promoting N-linked glycosylation of PD-L1, which stabilizes PD-L1 and increases its plasma-membrane localization, dampening CD8 + T-cell cytotoxicity. In immunocompetent mice, TRIM28 knockdown reduces tumor growth, lowers PD-L1 and increases CD8 + T-cell infiltration—effects reversed by SREBF1 overexpression; in an immune-augmented human PDX model, SREBF1 targeting synergizes with anti–PD-1 without overt toxicity. These findings identify a TRIM28–SREBF1–MGAT4A axis that couples lipid metabolic rewiring to immune-checkpoint regulation via PD-L1 N-glycosylation, positioning SREBF1 as a biomarker for BCa progression and risk stratification and as a druggable node to potentiate PD-1 blockade.