The Integrated Stress Response in Cancer: Paradox and Therapeutic Promise

The integrated stress response (ISR) is an evolutionarily conserved signaling pathway that converges diverse cellular stresses onto the eIF2α-ATF4 axis, thereby orchestrating a fundamental decision between adaptive survival and cell death. In cancer, malignant cells exploit the ISR to cope with microenvironmental pressure, yet strong or persistent ISR activation can also trigger apoptosis, highlighting its therapeutic potential. However, this duality complicates the targeting of the ISR for cancer therapy. In this review, we systematically outline the upstream regulators and downstream effector networks of the ISR, analyze its context-dependent functions, encompassing both tumor-promoting and tumor-suppressing activities, in tumorigenesis, immune modulation, and therapy resistance, and evaluate the rationale for targeting the ISR under defined conditions. We also comprehensively summarize and discuss recent advances in ISR-targeting agents, including both inhibitors and activators, under preclinical and clinical development, assessing their potential and current constraints. Although numerous challenges remain in therapeutically harnessing the ISR, we conclude that a deeper mechanistic understanding of how the ISR governs cell fate will further establish the ISR as a promising and actionable target for future cancer therapeutics.