Researchers at UC San Diego reported in a Cell paper that restoring protein recycling can reverse aspects of T-cell exhaustion in mice. The study, led by work from the lab of Ananda Goldrath, Ph.D., identified impaired proteostasis as a driver of dysfunctional tumor-infiltrating lymphocytes. The team reported that exhausted T cells showed breakdowns in recycling programs, with damaged and misfolded proteins accumulating. By restoring specific E3 ligases—NEURL3, RNF149, and WSB1—the researchers reported clearance of buildup and recovery of T-cell function that improved tumor killing. The work points to a more mechanistic path for next-generation immune checkpoint and T-cell rejuvenation strategies beyond checkpoint blockade alone.