TET2-mutant clonal hematopoiesis prevents T-cell exhaustion and suppresses cancer metastasis

Abstract

Clonal hematopoiesis (CH) is widely regarded as a risk factor for age-associated disease, yet its influence on solid tumor progression remains poorly understood. Here, we uncover an unexpected tumor-suppressive role for TET2-mutant CH in solid tumors. Through an analysis of over 16,000 cancer patients, we demonstrate that TET2 mutations are associated with a significant reduction in metastatic burden. Mechanistically, we show that Tet2 deficiency prevents terminal exhaustion in CD8+ tumor-infiltrating lymphocytes (CD8+ TILs). This resistance is driven by DNA hypermethylation at regulatory elements of the transcription factor Tox, which prevents the induction of the terminal exhaustion program. Consequently, Tet2-deficient CD8+ TILs maintain stem-like, effector-competent states that mediate durable anti-tumor immunity and suppress metastatic outgrowth. Our findings establish TET2-mutant CH as a natural epigenetic constraint on T-cell exhaustion and uncover a mechanistically defined pathway with translational potential for enhancing anti-tumor immune responses.