Tumor-specific memory-like progenitor exhausted CD8+ T cell subsets diverge into terminally exhausted cells and long-lived memory T cells

Chronic antigen stimulation induces CD8+ T cell exhaustion (TEX) in tumors. To investigate the developmental fate and heterogeneity of exhausted T cells, we generated an inducible Lag3^iCreERT2 Rosa26^LSL-tdTomato lineage-tracing mouse model and profiled lineage-traced CD8+ T cells isolated from tumors and peripheral lymphoid tissues at multiple time points following B16-F10 melanoma challenge. Single-cell RNA sequencing, paired TCR sequencing, and ATAC-seq were performed to characterize transcriptional, clonal, and epigenetic states of LAG3^+tdTomato^+, LAG3^-tdTomato^+, and corresponding control CD8+ T cell populations. These datasets provide a resource for studying the differentiation trajectories, clonal relationships, and chromatin remodeling underlying exhausted and memory-like tumor-reactive CD8+ T cells.