Cancer is one of the leading causes of death in the world, arising when cells accumulate genomic mutations that render them incapable of controlling their own proliferation and survival. While substantial improvements in patient outcome have been achieved over the years, completely eliminating tumorigenic cells remains a significant challenge, and some cancer types (such as pancreatic cancer) have not shown meaningfully improved patient survival rates despite our advancements in understanding cancer cell biology and treatment. Genetic targeting approaches to the treatment of cancer have yielded some success, but have shown rather disappointing results overall. In contrast to the diversity of genetic aberrations within tumor cells (making treatment difficult), cancers share common phenotypes that are more universally targetable. As cancers evolve within their biological environment to become aggressive, the net effects of their genetic alterations lead to 1) decreased sensitivity to cell death cues, 2) altered oxidative state and redox-dependent signaling, and 3) dramatically increased demand for energy production and biosynthesis (altered metabolism). The work of this study shows that in pancreatic cancer cells reversible metabolic adaptation alters oxidative stress sensitivity and triggers persistent drug resistance, demonstrating the interplay of the above three cellular activities. Further experimentation identifies the mitochondrial protein apoptosis-inducing factor (AIF) as an essential signaling node functioning at the convergence of all three of these processes. In response to cellular metabolic cues, AIF controls the ability of the mitochondria to produce energy required for tumorigenic growth, invasion, and survival while functioning as mitochondrial translation factor. Distinct from this pivotal metabolic role, AIF serves as a transmitter of extra-mitochondrial redox signaling cues regulating pro-tumor gene expression programs that are lethal without AIF. Finally, AIF exhibits involvement in atypical death pathways associated with the cell death regulators PGAM5 and XIAP. Remarkably, these AIF activities are functionally dissociable and demonstrate the multifunctional nature of AIF in control of tumorigenesis. Overall this study defines a variety of diverse AIF activities at the intersection of multiple tumorigenic phenotypes, furthering our understanding of how cancer cells converge upon different aggressive characteristics and revealing potential vulnerabilities for therapeutic intervention.