2
0The research highlights how the integrated stress response (ISR) acts as a primary catalyst for lung adenocarcinoma evolution and therapy resistance. By studying mouse models, scientists discovered that ISR activation allows cancer cells to transition from structured lung identities into highly undifferentiated and plastic states. This genetic reprogramming is driven by the p-eIF2α–ATF4 axis, which suppresses normal cellular identity while maintaining mitochondrial fitness and metabolic health. Conversely, blocking this response causes mitochondrial dysfunction and traps tumors in a less aggressive, more differentiated state. Ultimately, the study reveals that tumors exploit the ISR to survive the harsh microenvironment, correlating these findings with poor prognosis in human patients. This discovery positions the ISR as a critical target for future cancer therapies aimed at preventing tumor diversification.
References:
Diao S, Zou J Y, Wang S, et al. Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution[J]. Nature Cell Biology, 2026: 1-16.
