The integrated stress response (ISR) regulates cell fate during conditions of stress by leveraging the cell’s capacity to endure sustainable and efficient adaptive stress responses. Protein phosphatase 2A (PP2A) activity modulation has been shown to be successful in achieving both therapeutic efficacy and safety across various cancer models. However, the molecular mechanisms driving its selective antitumor effects remain unclear. Here, we show for the first time that ISR plasticity relies on PP2A activation to regulate drug response and dictate cellular survival under conditions of chronic stress. We demonstrate that genetic and chemical modulation of the PP2A leads to chronic proteolytic stress and triggers an ISR to dictate whether the cell lives or dies. More specifically, we uncovered that the PP2A-TFE3-ATF4 pathway governs ISR cell plasticity during endoplasmic reticular and cellular stress independent of the unfolded protein response. We further show that normal cells reprogram their genetic signatures to undergo ISR-mediated adaptation and homeostatic recovery thereby avoiding toxicity following PP2A-mediated stress. Conversely, oncogenic specific cytotoxicity induced by chemical modulation of PP2A is achieved by activating chronic and irreversible ISR in cancer cells. Our findings propose that a differential response to chemical modulation of PP2A is determined by intrinsic ISR plasticity, providing a novel biological vulnerability to selectively induce cancer cell death and improve targeted therapeutic efficacy.

综合应激反应 （ISR） 通过利用细胞承受可持续和有效的适应性应激反应的能力，在应激条件下调节细胞命运。蛋白磷酸酶 2A （PP2A） 活性调节已被证明在各种癌症模型中成功实现治疗效果和安全性。然而，驱动其选择性抗肿瘤作用的分子机制仍不清楚。在这里，我们首次表明 ISR 可塑性依赖于 PP2A 激活来调节药物反应并决定慢性压力条件下的细胞存活。我们证明 PP2A 的遗传和化学调节会导致慢性蛋白水解应激，并触发 ISR 来决定细胞是活还是死。更具体地说，我们发现 PP2A-TFE3-ATF4 通路在内质网和细胞应激期间控制 ISR 细胞可塑性，与未折叠的蛋白质反应无关。我们进一步表明，正常细胞对其遗传特征进行重编程以经历 ISR 介导的适应和稳态恢复，从而避免了 PP2A 介导的应激后的毒性。相反，PP2A 的化学调节诱导的致癌特异性细胞毒性是通过激活癌细胞中的慢性和不可逆的 ISR 来实现的。我们的研究结果表明，对 PP2A 化学调节的不同反应是由内在的 ISR 可塑性决定的，提供了一种新的生物脆弱性来选择性诱导癌细胞死亡并提高靶向治疗效果。