TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1.

Abstract

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 Texprog differentiation into Texint/eff and further drives functional Tex cells into a fully dysfunctional Texterm 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 expands the anti-PD-1-responsive Texprog cells, and enhances the persistence of functional CD8+ T cells. Our findings suggest targeting lnc-SUMF2-8 could enhance the anti-tumor CD8+ T-cells function and synergistically improve the efficacy of anti-PD-1 treatment and CAR-T cell therapies.