Age-independent and targetable transcription factor networks regulating CD8⁺ T cell senescence in aging humans

The age-related decline in immunity is accompanied by the accumulation of senescent CD8⁺ T cells. Using senescent cell isolation coupled with multi-omics profiling, we reveal the transition to senescence to be controlled by chromatin state-specific transcription factor (TF) networks in younger and older donors independent of age. These TF networks mediate widespread enhancer remodeling, repressing cell identity genes while upregulating inflammatory and secretory pathways. Inhibition or downregulation of AP1, KLF5, or RUNX2 modulates the transcriptional output and partially restores the blunted response to stimulation of senescent CD8⁺ T cells. Senescent CD8⁺ T cell gene signatures also predict responsiveness to chimeric antigen receptor (CAR)-T cell therapy in diffuse large B cell lymphomas. Overall, our study defines the gene-regulatory mechanisms underlying human CD8⁺ T cell senescence, highlights TF network perturbation as a viable strategy to manipulate the senescence state, and identifies senescent CD8⁺ T cell gene signatures as prognostic tools for immunotherapy outcome.