UC San Diego scientists reported in Cell that impaired protein recycling programs help drive T-cell exhaustion in mice. The study identifies a proteostasis failure in exhausted T cells, where damaged and misfolded proteins accumulate due to disrupted recycling machinery. The researchers demonstrated that a “tag and sort” approach—using E3 ligase activity—can clear misfolded proteins and restore T-cell function. They pointed to NEURL3, RNF149, and WSB1 as E3 ligases involved in rescuing recycling pathways. By reversing exhaustion in preclinical models, the findings add a mechanistic lever beyond existing exhaustion-targeting strategies that focus on signaling checkpoints or metabolic pathways.