TRIM14 recruits BRCC3 to stabilize PD-L1 by suppressing p62-dependent selective autophagy in glioma

Glioma remains largely refractory to immune-checkpoint blockade, in part because tumor-intrinsic mechanisms sustain programmed death-ligand 1 (PD-L1) and reinforce an immunosuppressive microenvironment. Tripartite motif-containing 14 (TRIM14) is an immune associated protein. However, the role of TRIM14 in PD-L1 homeostasis in glioma is incompletely defined. Here we reported that TRIM14 was increased in malignancies and was particularly associated with overall survival in glioma. Single-nucleus analysis showed that TRIM14-positive nuclei were predominantly malignant, indicating association between TRIM14 and glioma progression. We also found TRIM14 upregulated PD-L1 protein levels without materially changing CD274 mRNA in glioma cells. Additionally, knockout of TRIM14 reduced tumor growth in vivo. Mechanistically, TRIM14 recruits deubiquitinase BRCC3 to reduce K63-linked ubiquitination of PD-L1 in glioma cells, thereby inhibiting p62-mediated autophagic degradation of PD-L1. This pathway prompts that TRIM14 or BRCC3 maybe candidate targets for therapeutic intervention in glioma.