Targeting the integrated stress response to overcome cancer therapy resistance: From mechanisms to therapeutic opportunities.

Drug resistance remains a major obstacle in cancer therapy, underscoring the urgent need to identify new targets and therapeutic strategies to overcome resistance. The integrated stress response (ISR), an evolutionarily conserved mechanism that enables cells to adapt to various internal and external stresses, plays a critical role in determining cell fate and has emerged as a key player in therapy resistance. However, targeting the ISR to overcome treatment resistance remains challenging. In this review, we systematically outline the regulatory mechanisms of the ISR in cancer cells and its crosstalk with other oncogenic signaling pathways. We further summarize the molecular mechanisms by which ISR signaling contributes to therapeutic resistance, along with recent advances in targeting the ISR and the current landscape of drug development. In addition, we explore the potential of leveraging ISR-induced cell death pathways to sensitize tumors to therapy and overcome resistance. We also discuss the current status, challenges, and future directions for clinical translation of ISR-targeting strategies, and provide perspectives aimed at advancing their therapeutic application.