Abstract The number of cancer patients being treated with checkpoint blockade immunotherapy (CBI) targeting the PD- 1/PD-L1 pathway is increasing dramatically. Recently a novel and unfavorable response pattern termed hyperprogression (HPD) has been identified which is characterized by a rapid worsening and acceleration of tumor growth after starting CBI. Our group was the first to report the genetic alterations associated with HPD, namely MDM2 amplifications and EGFR alterations. However, mechanisms of action or strategies to circumvent HPD have not been reported. Using novel tumor models, our preliminary data has identified that MDM2 amplified cells are hypersensitive to TNFα induced proliferation compared to non-MDM2 amplified tumor lines. Mechanistically we have identified that MDM2 amplification dramatically alters TNF-alpha signaling pathways, blocking apoptotic signals while simultaneously promoting NFκβ mediated cell growth and proliferation. In this study we will elucidate mechanisms of HPD and determine whether MDM2 amplification alone is sufficient to cause HPD and whether HPD can occur with other checkpoint blockade agents. We will then test whether novel MDM2/4 or TNFα inhibitors can block or prevent HPD in our unique tumor models. Our hypothesis that MDM2 amplified tumors are resistant to TNF-alpha induced apoptosis and hypersensitive to TNFα induced cell cycling which results in uncontrolled proliferation and HPD after treatment with CBI. Together these studies will significantly improve our mechanistic understanding of HPD and identify targeted drug strategies that can be rapidly translated into clinical trials to improve outcomes in cancer patients treated with CBI.