Researchers at UC San Diego reported in a new Cell study that reversing T-cell exhaustion in mice may hinge on restoring impaired cellular protein recycling. The work identifies proteostasis breakdown as a culprit behind accumulation of damaged and misfolded proteins in exhausted T cells. The study points to a “tag and sort” repair approach driven by specific E3 ligases, including NEURL3, RNF149, and WSB1. Restoring these recycling enzymes cleared misfolded protein buildup and improved T-cell function, with enhanced tumor control in the mouse models. The findings broaden the immunotherapy mechanism space beyond checkpoint blockade by suggesting that intracellular quality-control circuits can be therapeutically modulated to reinvigorate anti-tumor immunity.