Abstract: ISG15, an interferon-stimulated gene product, has been recognized predominantly for its antiviral capabilities. However, the effect of ISG15 on cell survival remains unclear and requires experimental investigation. Our study revealed that ISG15, which is secreted by bone marrow-derived macrophages (BMDMs), has the capacity to induce apoptosis in CD8⁺ T cells. Notably, we discovered that the proapoptotic effects of ISG15 are facilitated through its interaction with the opioid growth factor receptor (OGFR). This apoptotic pathway can be significantly attenuated by treatment with the opioid antagonist naltrexone. Our findings illuminate a previously uncharacterized ISG15-mediated pathway that regulates CD8⁺ T cell apoptosis, thereby highlighting the critical role of ISG15 in the orchestration of the innate immune response.