Hypoxia-driven perturbations of proteostasis and therapeutic vulnerabilities in cancer

Solid tumors are characterized by chaotic architecture and abnormal vasculature, which trigger rapid cell proliferation leading to steep oxygen gradients, and render the tumor core highly hypoxic or anoxic. These hypoxic regions within a tumor profoundly drive cancer progression by stabilizing key transcription factors, Hypoxia-Inducible Factors, HIF-1 and HIF-2. In addition to the well-established HIF pathways, hypoxic areas in tumors are being increasingly examined for their capacity to disrupt proteostasis, specifically influencing oxygen-dependent protein folding in the endoplasmic reticulum. Hypoxia acts as a key stressor, leading to the accumulation of misfolded proteins, triggering Unfolded Protein Response as a compensatory mechanism, mediated by the three main ER sensors: PKR-like ER kinase, Inositol-Requiring enzyme 1, and Activating Transcription factor 6. In a healthy cell, UPR typically seeks to induce cell death, reestablishing cellular equilibrium. Cancer cells subvert this response by utilizing it to their advantage, enhancing metabolic flexibility, evading immune surveillance, and establishing resistance. There is growing evidence that these hypoxia-induced misfolded proteins contribute to the progression of tumors by causing genomic instability and dysregulating oncogenic signaling. This chapter details how hypoxia regulates protein misfolding, leading to cancer cell adaptation, and outlines relevant therapeutic targets.