UPF1 attenuates CD8⁺ T cell exhaustion in glioma by destabilizing CD52 mRNA

CD8⁺ T cell exhaustion has emerged as a challenge for progression and immunotherapy in nearly all of tumors including glioma. Recent studies revealed that UPF1 might play a suppressive role in glioma progression, however the underlying mechanism is unclear. Here, exhausted CD8⁺ T cells (CD8⁺ Tex) and total CD8⁺ T cells were isolated from PBMCs of glioma patients and healthy volunteers. We found that UPF1 was downregulated in CD8⁺ Tex compared to total CD8⁺ T cells. Glioma patients with elevated UPF1 expression in CD8⁺ T cells showed significantly prolonged overall survival. CD8⁺ T cells, or those with UPF1 overexpression/silencing, were co-cultured with U251 glioma cells to evaluate their impact on U251 cell malignant progression. UPF1 overexpression enhanced CD8⁺ T cell anti-tumor activity by promoting anti-tumor cytokine secretion and suppressing immune checkpoint factor expression. Mechanistically, UPF1 bound to CD52 mRNA, reducing its stability and protein levels, thereby alleviating CD52-mediated CD8⁺ T cell exhaustion. CD52 overexpression reversed the anti-tumor effects of UPF1 on CD8⁺ T cells. An in situ glioma mouse model was established by injecting GL261 cells into the ventricles of wild-type (WT) and T cell-specific UPF1 conditional knockout (UPF1 cKO) mice. UPF1 cKO mice showed increased tumor burden compared to WT mice, which was rescued by UPF1 restoration. In conclusion, UPF1 attenuates CD8⁺ T cell exhaustion and suppresses glioma progression by destabilizing CD52 mRNA.