A trade-off between stress resistance and tolerance underlies the adaptive response to hydrogen peroxide.

Physiological adaptation to environmental stress involves distinct molecular responses leading to either stress resistance, which maintains proliferation by degrading the stressor's effects, or tolerance, which prioritizes survival over proliferation. While these strategies are complementary, their coordination remains unclear. Using microfluidics and live-cell imaging, we investigated the genetic basis of their interplay during the response to hydrogen peroxide (H₂O₂) in budding yeast. We found that deleting zwf1Δ, which controls NADPH synthesis via the pentose phosphate pathway (PPP), reduced resistance but unexpectedly enhanced tolerance to H₂O₂. This trade-off was further characterized through genetic and environmental interventions and found to be conserved in bacteria. Our results support a model in which redox signaling shifts cells to a nutrient-dependent tolerant state via protein kinase A inhibition when the H₂O₂ homeostatic response is overwhelmed. This framework could inform synergistic therapies targeting resistance and tolerance to prevent drug escape and disease relapse. A record of this paper's transparent peer review process is included in the supplemental information.