ABSTRACT Tumor hypoxia reduces the effectiveness of anti-cancer treatment with radiotherapy, some chemotherapy and immune checkpoint blockade therapy. For radiotherapy, biophysical measures show that hypoxic cells require 2.8-fold greater dose to achieve the same cell kill as those that are fully oxygenated. For immunotherapy, hypoxia has been shown to contribute to immune evasion and even accelerate T cell exhaustion. For these reasons, many groups have tried to deliver more oxygen to tumors as an adjuvant to increase tumor sensitivity. Unfortunately, this approach has met with disappointing clinical results. We have looked at tumor oxygenation differently, as a supply and demand mismatch, with the supply being inadequate to meet the demand of the growing tumor mass. Therefore, if we could reduce oxygen demand rather than increase supply, we could effectively reduce hypoxia and sensitize tumors. Because mitochondria are the major sink for oxygen within a cell, we propose that novel mitochondria inhibitors would reduce oxygen demand to match the limited supply. We have identified papaverine (PPV) as an FDA-approved molecule with the ability to inhibit mitochondrial function at clinical doses. Published studies from our group showed that in mouse tumors that papaverine can radiosensitize through inhibition of mitochondrial function, producing “Metabolic Radiosensitization”. Papaverine was originally isolated from the poppy and used as a smooth muscle vasorelaxant presumably due to inhibition of phosphodiesterase 10A. This activity makes it an effective drug for cerebral vasospasm, but causes a systemic drop in blood pressure and potential adverse cardiovascular effects. We therefore propose in this application to synthesize and evaluate new small molecule derivatives of papverine that we have designed to remove its activity as a phosphodiesterase inhibitor, but retain its activity as a mitochondrial complex 1 inhibitor. Using these PPV derivatives, and sophisticated mouse models of cancer, we intend to prove that inhibition of mitochondrial function is an effective strategy for removing hypoxia in solid tumors without affecting well oxygenated normal tissue. Preliminary data supports the overall theory that mitochondrial inhibitors increase tumor oxygenation and sensitivity to radiotherapy and immune checkpoint blockade therapy.