Longevity & AgingTET2 Mutations Drive Aging Blood Clones, Inflammation and Divergent Cancer Immunotherapy Outcomes
TET2 is an enzyme that removes methyl tags from DNA, and its loss-of-function mutations are among the most common drivers of age-related clonal hematopoiesis (CHIP). This narrative review argues that TET2 acts as a context-dependent regulator, not just a demethylase. Its effects depend on cell type, direction of alteration, functional layer (catalytic, scaffold-like, metabolic) and microenvironment. In blood stem cells, TET2 loss favors clonal expansion and myeloid skewing. In macrophages, it amplifies NLRP3, IL-1β and IL-6 signaling, which is linked to atherosclerosis and heart failure. In solid tumors and CAR-T cells, effects vary, with possible benefits for T-cell persistence but long-term clonal risk. Human evidence is mostly associative; mechanisms come largely from animal and cell models.
