IFN-γ Engineering Renders Tumor Cells Autonomous and Bystander Tumoricidal Activities

Cancer remains a major public health challenge worldwide. Tumor reprogramming has emerged as a novel therapeutic strategy for cancer treatment. However, despite increasing interest in this approach, whether tumor cells can be stably and efficiently reprogrammed into cytotoxic effector cells remains unclear. Here, we engineered multiple types of tumor cells to overexpress T cell effectors including IFNG, FASLG, or PRF1/GZMB and evaluated their cytotoxic potential. We found that tumor cells engineered to overexpress these genes can inhibit cell autonomous proliferation in vitro. Co-culture assays showed that overexpression of IFNG or FASLG enabled tumor cells to kill neighboring tumor cells, whereas PRF1/GZMB overexpression had no such effect. However, the cytotoxic effect mediated by IFNG overexpression was much stronger than that mediated by FASLG overexpression. Moreover, IFNG overexpressing tumor cells suppressed the growth of wild-type tumor cells without evident toxicity in vivo. These findings establish a potent strategy for reprogramming tumor cells to acquire tumor-killing activity and suggest a potential new direction for cancer therapies.