Epigenetic aging in the tumor microenvironment: mechanisms and implications for immunotherapy

Aging reshapes the tumor microenvironment (TME) by altering the immune, stromal, and vascular compartments, yet these changes are not fully explained by chronological age. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA programs, may contribute to persistent alterations in cellular function and communication. In this review, we synthesize current evidence on epigenetic remodeling in the aged TME, distinguishing established findings in aging and cancer from mechanisms that remain to be demonstrated specifically in aged tumors. We highlight how epigenetic changes intersect with cellular senescence, chronic inflammation, and metabolic stress to weaken antitumor immunity and influence treatment response, with particular attention to T-cell dysfunction, regulatory T-cells, myeloid cells, fibroblasts, and endothelial cells. We also discuss the limitations of bulk-tissue epigenetic clocks and the emerging value of cell-resolved and spatial analyses. Finally, we consider therapeutic implications, including epigenetic therapies, senescence-directed interventions, and selective targeting of suppressive immune-stromal interactions, while noting that their ability to reverse TME aging remains uncertain. Integrating longitudinal human studies with functional experiments will be essential to determine whether epigenetically altered immune-stromal niches can serve as biomarkers or therapeutic targets beyond chronological age alone.