p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells

Abstract

Adoptive T-cell therapies using chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) have transformed cancer treatment but remain limited by poor persistence and progressive T-cell exhaustion. Manufacturing strategies that promote memory T-cell formation may improve therapeutic durability. Here we investigated whether transient pharmacologic activation of the p53 pathway influences the differentiation and function of human CD8+ T cells. p53 expression was minimal in quiescent naïve CD8+ T cells but was rapidly induced following T-cell receptor activation. Pharmacologic inhibition of the p53 negative regulator MDM2 increased p53 protein levels and promoted expansion of central memory and stem-like memory T-cell subsets during clonal proliferation. Treated cells displayed enhanced mitochondrial fitness, increased polyfunctional cytokine production, and transcriptional programs consistent with memory differentiation and reduced exhaustion. Importantly, TCR-engineered CD8+ T cells generated in the presence of the MDM2 inhibitor Navtemadlin demonstrated superior tumor-cell killing in vitro compared with conventionally manufactured cells. These findings identify transient p53 activation as a pharmacologic strategy to enhance memory programming during T-cell manufacturing and suggest a clinically feasible approach to improve the efficacy of adoptive T-cell immunotherapies.