ONC212 is a second-generation imipridone compound under investigation for cancer therapy, particularly for refractory or relapsed tumors such as diffuse midline gliomas and other hard-to-treat cancers. It activates the integrated stress response (ISR) pathway by promoting PERK-mediated phosphorylation of eIF2α, leading to translational repression and selective induction of apoptosis in cancer cells while sparing normal cells. Preclinical studies demonstrate its efficacy in overcoming resistance to first-generation imipridones like ONC201. Researchers are exploring its potential in combination therapies to enhance antitumor activity and its effects on the tumor microenvironment, including immune modulation, to improve outcomes in various solid tumors.