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Summary The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy., Graphical Abstract, Highlights • iPSC-derived rejuvenated CTLs are effective against EBV-induced tumors in vivo • Rejuvenated CTLs are implemented with an inducible caspase-9 (iC9)-based suicide system • Upon induction, the iC9 system efficiently leads to apoptosis in rejuvenated CTLs • The iC9-based system provides a safeguard for future iPSC-mediated cell therapy, In this article, Nakauchi and colleagues show that iPSC-derived rejuvenated CTLs (rejCTLs) implemented with an inducible caspase-9 (iC9)-based suicide system are effective against EBV-induced tumors in vivo. Upon induction, the iC9-based system efficiently and safely leads to apoptosis in these rejCTLs in vitro and in vivo and provides a safeguard for future iPSC-mediated cell therapy.