The embryonic stem cell (ESC) microenvironment can promote the proliferation of terminal cells and reduce the invasiveness of tumor cells. However, implanting ESCs directly in vivo can result in tumorigenicity, immune rejection after differentiation, and graft-versus-host reaction. Therefore, safety is very important in the clinical application of ESCs. We injected ESCs modified with a suicide gene into a leukemia mouse model through peripheral blood to observe the treatment effectiveness. In addition, according to the pre-test, we set the time point of differentiation after transplantation and then activated the suicide gene to kill the ESCs that we had initially implanted, hoping to avoid the risks mentioned earlier. Our results indicated that the body weight and survival rates of mice treated with an ESC microenvironment increased, and leukemic cells in peripheral blood and bone marrow decreased compared with untreated mice. There was no obvious teratoma in mice that received ESC therapy and induced the suicide gene at the proper time during the observation period, while an apparent teratoma was observed in the lungs of mice which received ESC therapy and never induced the suicide gene. Therefore, the ESC microenvironment can promote self-healing of the in vivo microenvironment. Inducing the suicide gene at the appropriate time can reduce or even avoid tumorigenicity and immune rejection after transplantation of ESCs in vivo and improve the safety of their clinical application.