The unscheduled proliferation of cancer cells outside their natural niches subjects the cells to multiple insults, such as metabolic aberrations, detachment from the extracellular matrix (ECM), hypoxia, and immune cell attacks. Oxidative stress is a hallmark of cancer because these insults can all lead to the accumulation of reactive oxygen species (ROS) including H₂O₂. However, it remained largely elusive how cancer cells are able to adapt to harsh oxidative environments. In this symposium, we first provide evidence that cancer cells co-opt the neuronal ROS-sensing channel TRPA1 (Takahashi N, Nature Chem. Biol. 2011) to tolerate highly oxidative environments by activating Ca²⁺-induced anti-apoptotic programs (Takahashi N, Cancer Cell 2018). We then introduce a tumor-targeted H₂O₂ probe (called “T-AP1”) that we recently developed. T-AP1 not only revealed intratumor H₂O₂ heterogeneity but also identified a novel and surprising oxidative-stress defense mechanism in cancer. Thus, our works provide a significant advance in our understanding of adaptation mechanisms to oxidative stress, which represents a substantial hurdle that impedes tumor initiation and progression.