Cancer cell survival is often challenged by various physiological and microenvironmental stresses, including oxidative stress, hypoxia, nutrient deprivation, and DNA damage. Each stressor can be potentially lethal unless cancer cells are able to adapt to it. Stress adaptation via clonal selection is postulated to underlie the acquisition of aggressive phenotypes, including chemoresistance and metastatic capacity.

Previous studies have demonstrated a number of methods that cancer cells exploit for adaptation and survival under adversity. For instance, NRF2 is a crucial factor for the maintenance of redox balance under stress, and KEAP1 is a key negative regulator of NRF2 that targets it for proteasomal degradation. Both NRF2 and KEAP1 are found to harbor various mutations that block their interaction, which sustains high levels of NRF2 to promote malignant progression. HIF-1/2 promotes angiogenesis, cell survival, glucose metabolism, and metastasis; although HIF-1/2 proteins are normally induced under hypoxia, cancer cells can exploit multiple mechanisms to boost the synthesis and/or stabilization of HIF-1/2 proteins under normoxia. Importantly, increasing evidence in the literature suggests that an overlooked component of stress adaptation occurs through acute changes in mRNA translation and protein synthesis. Under stress, cancer cells attenuate global mRNA translation to preserve energy, while maintaining selective translation of mRNAs that support survival under stress. However, our understanding of how cancer cells cope with these stresses remains incomplete. Delineation of the key mechanisms underlying stress adaptation may reveal the “Achilles’ heel” of cancer, and blockade of these processes represents an attractive therapeutic approach.

This special issue aims to focus on the identification of important regulators and pathways that facilitate cancer cells to escape stress-induced cell death. Original papers as well as review articles relevant to this topic are both welcomed.

Potential topics include but are not limited to the following:

• Identification of drugs and compounds that preferentially induce stress levels in cancer cells, such as reactive oxygen species (ROS)
• Mechanisms underlying cancer cell survival in stressful conditions, such as oxidative stress, hypoxia, heat shock, and nutrient deprivation
• Mechanisms that drive chemoresistance, radioresistance, and hormonal resistance (e.g., in breast and prostate) in cancer cells and the identification of significant prognostic markers that are associated with these processes
• Strategies to target the stress adaptation in cancer cells, such as screening and identification of drugs and compounds that sensitize cancer cells to physiological and environmental stresses
• Review articles that provide an overview of novel insights into the relevant findings in the research aspects listed above