In vitro PI3Kδ inhibition skews CD8 T cell differentiation towards progenitor exhaustion in vivo and reprograms tumor microenvironment metabolism, immune composition, and inflammation [scRNA-seq]

In vitro PI3Kδ inhibition using Idelalisib (CAL-101) drives CD8 T cells toward a progenitor exhausted (Tpex) phenotype while resisting terminal exhaustion in vitro. We performed single-cell RNA sequencing and spatial transcriptomics on B16-melanoma tumors and show that CAL-101-treated T cells enhance oxidative phosphorylation, proliferation, and Ifnγ responsiveness. The CAL-101 treated cells deeply infiltrate tumors and upregulate the CXCR3-CXCL10 axis, coinciding with reduced tumor-associated macrophage signatures and increased pro-inflammatory signaling in the tumor microenvironment. CAL-101 reprograms T cell fate and remodels the TME, offering insight into how to improve immunotherapeutic efficacy for solid tumors.