Nanoscale artificial antigen-presenting cells reveal metabolic interventions modulate clonal composition of CD8+ T cells.

In response to pathogens, CD8+ T cells reprogram their metabolism to fuel a proliferative burst of antigen-specific T cells. Engineering metabolism can augment CD8+ T cell responses, yet mechanistic studies understanding the direct impact of metabolic programming on T cell phenotype and TCR receptor (TCR) repertoire selection remains unknown. Here, using nanoparticle-based artificial antigen presentation cells (aAPCs) as a model of endogenous expansion to stimulate primary murine CD8+ T cells, we show that glutamine antagonism modulates epitope-specific T cell phenotype by upregulating self-renewal markers and serves a new function as a "clonal filter," enriching high-affinity CD8+ T-cell clones. Moreover, the effect of glutamine inhibition skews towards cells with high-affinity TCRs and enhances their ability to kill in vivo. Collectively, these findings introduce metabolic blockade as a rapid, non-genetic strategy to pre-select durable, high-affinity T cells, providing an easily implementable add-on for adoptive cell therapy.