Researchers at UC San Diego reported in Cell that restoring impaired protein recycling can reverse T-cell exhaustion in mouse models. The work, led by Ananda Goldrath’s lab, links proteostasis failures to accumulation of damaged proteins in exhausted T cells. In the study, investigators used a “tag and sort” strategy by reactivating E3 ligases involved in the recycling program. They identified specific E3 ligases—NEURL3, RNF149, and WSB1—as key to clearing misfolded protein buildup and restoring tumor-clearing function. The findings provide a mechanistic target set for future immune-stimulation approaches, particularly for cancer immunotherapy scenarios where T cells become dysfunctional over time.