Purpose: Low-dose DNA demethylating agent decitabine therapy is effective in a subgroup of cancer patients. It remains largely elusive for the biomarker to predict therapeutic response and the underlying anti-tumor mechanisms, especially the impact on host anti-tumor immunity.<br />Experimental Design: The influence of low-dose decitabine on T cells was detected both in vitro and in vivo. Moreover, a test cohort and a validation cohort of advanced solid tumor patients with low-dose decitabine-based treatment were involved. The activation, proliferation, polarization, and cytolysis capacity of CD3+ T cells were analyzed by FACS and CCK8 assay. Kaplan-Meier and Cox proportional hazard regression analysis were performed to investigate the prognostic value of enhanced T cell activity following decitabine epigenetic therapy.<br />Results: Low-dose decitabine therapy enhanced the activation and proliferation of human IFN-+ T cells, promoted Th1 polarization and activity of cytotoxic T cells both in vivo and in vitro, which in turn inhibited cancer progression and augmented the clinical effects of patients. In clinical trials, increased IFN-+ T cells and increased T cell cytotoxicity predicted improved therapeutic responses and survival in the test cohort and validation cohort.<br />Conclusions: We find that low-dose decitabine therapy promotes anti-tumor T cell responses by promoting T cell proliferation and the increased IFN-+ T cells may act as a potential prognostic biomarker for the response to decitabine-based anti-tumor therapy.