TOX 诱导的 lnc-SUMF2-8 通过溶酶体依赖性降解 TCF-1 削弱 CD8⁺ T 细胞的抗肿瘤功能和抗 PD-1 反应

The reduction of TCF-1 during CD8 + T cell exhaustion leads to attenuated antitumor activity and diminished responsiveness to immune checkpoint inhibitors.

However, how TCF-1 is downregulated remains unclear. Here, we showed that during CD8 + T cell exhaustion, lnc-SUMF2-8, induced by transcription factor TOX, can bind to cytosolic TCF-1 and direct it to the lysosome for degradation. The reduction of TCF-1 promotes Tex prog differentiation into Tex int/eff and further drives functional Tex cells into a fully dysfunctional Tex term state.

We demonstrated that TCF-1 reduction during T cell exhaustion is initiated by lnc-SUMF2-8-dependent lysosomal degradation of TCF-1 protein, followed by transcriptional suppression of TCF7 mRNA. Deletion of lnc-SUMF2-8 blocks lysosomal TCF-1 degradation, which maintains stable TCF-1 levels in Tex cells, thereby expanding the anti-PD-1-responsive Tex prog cells and enhances the persistence of functional CD8 + T cells.

Our findings suggest that targeting lnc-SUMF2-8 could enhance the function of the antitumor CD8 + T cells and synergistically improve the efficacy of anti-PD-1 treatment and CAR-T cell therapies.