Determining changes in the oxidized proteome of human CD8+ T cells with enhancing proteasome activity

Chronic T cell receptor (TCR) stimulation, combined with adverse conditions in the tumor microenvironment (TME) such as hypoxia and nutrient deprivation, frequently results in T cell exhaustion. Exhausted T cells (TEX) experience oxidative stress, which causes an accumulation of oxidized proteins within the cells. We hypothesized that oxidized protein formation might exceed proteasomal degradation capacity, leading to their accumulation and impairing TEX cell fitness. By pharmacologically boosting proteasome activity, we decreased the accumulation of oxidized proteins, delaying T exhaustion and enhancing T cell fitness, resulting in superior anti-tumor control.