Transcriptional and Epigenetic Regulation of T Cell States in Cancer

CD8 + T cells are central to effective antitumor immunity, yet in cancer, they often undergo progressive transcriptional, epigenetic, and metabolic reprogramming that leads to an exhausted state and limits current immunotherapy. A deeper understanding of the molecular mechanisms that govern CD8 + T cell differentiation and function within the tumor microenvironment is essential to overcome this barrier. This review outlines the current knowledge of the transcriptional and epigenetic programs that shape T cell heterogeneity in cancer and chronic infection, with a focus on the formation and maintenance of exhausted T cell subsets. We highlight how T cell–intrinsic factors such as transcription factors and chromatin regulators and extrinsic factors such as nutrient availability converge to influence T cell fate decisions and function, as well as how these are affected in cancer. Finally, we discuss emerging therapeutic strategies aimed at reprogramming the epigenome to restore T cell function, offering new avenues to enhance the efficacy and durability of cancer immunotherapy.