Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8⁺ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.

Epigenetic therapy;Immune checkpoint blockade;Combination therapy;T cell exhaustion;Immune macroenvironment;Spatial immune contexture;Immunometabolism;Cancer microbiome