A small molecule drug screening identifies colistin sulfate as an enhancer of Natural Killer cell cytotoxicity

Because of their crucial role in tumor immunity, NK cells have quickly become a prime target for immunotherapies, with adoptive transfer of NK cells and the use of NK cell engagers quickly moving to clinical stage. On the other hand, only few studies have focused on small molecule drugs capable of unleashing NK cell against cancer. In this context, repurposing small molecule is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we screened 1,200 FDA-approved drugs from the Prestwick Chemical Library, to identify compounds that increase NK cell cytotoxic potential. Using a high-throughput luciferase-release cytotoxicity assay, we found that the antibiotic colistin sulfate increased cytotoxicity of human NK cells towards cancer cells. The effect of colistin was short lived and was not observed when NK cells were pretreated with the drug, showing how NK cell activity was potentiated only when the compound was present at the time of recognition of cancer cells. Further studies are needed to uncover the mechanism of action and the pre-clinical efficacy of colistin sulfate in mouse cancer models. ### Competing Interest Statement JSD is an inventor on patents licensed to Turnstone Biologics, which is commercializing oncolytic Maraba virus. JSD has patents licensed and also holds equity in Virica Biotech, which is developing oncolytic virus platforms. MA has a consulting agreement with Alloy Therapeutics and a sponsored research agreement with Dragonfly Therapeutics and Actym Therapeutics.