Treatment implications of T cell DNA damage in anti-tumor immunity

T cell activity is fundamental to effective immunotherapies and sustained tumor control. Recent studies have demonstrated that the therapeutic potential of T cells is notably affected by DNA damage dynamics. Notably, DNA damage within T cells is both a predictive biomarker for therapeutic responses and a druggable vulnerability whose modulation enhances the anti-tumor efficacy of immunotherapies and targeted treatments. This review is aimed at assessing current understanding of the origins of DNA damage in T cells, its consequences, and therapeutic implications within the tumor microenvironment and during anticancer treatment. By elucidating the mechanisms through which DNA damage dictates T cell fate and function, we highlight its dual role as a biomarker and a therapeutic target. Our goal is to accelerate the optimization of immunotherapeutic regimens and the development of combinatorial approaches leveraging a dynamically regulated immune microenvironment by integrating T cell-intrinsic DNA damage response into patient stratification and trial design, together with rational optimization of genotoxic therapies and immunotherapy, to enable a durable response while minimizing immune toxicity.