PROJECT SUMMARY/ABSTRACT My long-term goal is to lead a translational cancer research lab at a major research institution. Throughout my predoctoral work, I have cultivated expertise in studying intracellular trafficking in multiple contexts including cancer metabolism, phosphatase signaling, and nucleotide-based drug delivery. My overall objective in this application is to complete my ongoing studies and then leverage my experience studying endolysosomal trafficking to address critical open questions in cancer immunology during my postdoctoral work. For the F99 phase, I will complete studies evaluating small molecules that target intracellular trafficking as antisense oligonucleotide (ASO) potentiating agents in tumors and normal tissues. ASO are 16-20 bp nuclease-resistant oligonucleotides that base pair with a target RNA and can elicit its degradation or alter its splicing. Therefore, ASO are the ultimate platform technology that could cripple lethal, drug-resistant tumors by targeting “undruggable” oncogenes. Poor uptake into tumor cells currently limits the clinical use of ASO in cancer patients. By bringing a cell biology background to this field, which is populated primarily by biochemists, I have identified 4 novel proteins that when targeted increase ASO activity by an unprecedented 100-fold. For the K00 phase, I will continue to study endolysosomal trafficking, but shift my focus from ASO delivery to resistance mechanisms to cancer immunotherapies. The rationale underlying the proposed training plan is that the critical trafficking steps necessary to deliver ASO to the cytoplasm of tumor cells have also been implicated in anti- tumor immunity. Combining my expertise in intracellular trafficking and technical skills in advanced imaging with deep knowledge gained from working in a cancer immunology lab is likely to produce significant advances in this field. Completing these studies will also allow for me to develop a niche in this highly competitive field that I could expand upon in my own independent research lab. The overall training objective in this application is to develop and cultivate the management, networking, immunology expertise, and writing skills that are necessary to be successful in a postdoctoral fellowship and as an academic PI at a major research institution. The Training Plan addresses these training goals by taking advantage of critical resources provided by UCI and its vibrant, collaborative cancer research community.