SUMMARY Oral squamous cell carcinoma (OSCC) is the most common oral malignancy and subtype of head and neck cancer and frequently identified by dentists during routine care. OSCC is the sixth most common cancer globally with incidence continuing to rise. Current therapies for OSCC are inadequate and OSCC are resistant to immune checkpoint inhibition (ICI), resulting in frequent reoccurrence and poor rates of patient survival. The development of targeted therapies for OSCC is hampered by the lack of common driving oncogene mutations, but inactivation of the p53 tumor suppressor is frequent in human papillomavirus (HPV) negative OSCC, which contributes to treatment resistance, immune cell suppression, and reduced patient survival. Therefore, new and innovative treatment approaches are desperately needed for OSCC and particularly those with inactivated p53. Thus, we sought to identify new vulnerabilities in HPV-negative OSCC. It was believed that if p53 was inactivated, cancer cells did not require Mdm2, which binds and regulates p53. However, challenging this long-held belief, our results with cancers arising in p53-null mice showed that the Mdm2 oncogene was required for the survival of p53-null murine cancers. Capitalizing on our paradigm-shifting discovery in mice, our preliminary data reveal Mdm2 is a previously unknown and unexpected vulnerability in p53-inactivated human OSCC. We propose that targeted loss of Mdm2 will effectively eliminate OSCC cells by activating p53- independent mechanisms that signal for apoptosis and pathways that contribute to increasing immunogenicity. Preliminary results with a novel Mdm2-targeted degrader we designed and synthesized support this hypothesis. To further test our hypothesis, we propose to 1) investigate the cytotoxicity mechanism(s), the required pathways, and in vivo efficacy with targeted Mdm2 loss with our Mdm2 PROTAC in OSCC cells with various p53 alterations; and 2) investigate improving the immunogenicity of OSCC tumors and overcoming ICI resistance with several approaches that include our Mdm2 PROTAC and immune competent syngeneic mouse models. Completion of this study will uncover the specific requirements of Mdm2 in OSCC, significantly increasing the mechanistic understanding of the p53-independent functions of Mdm2, and provide critical pre-clinical evaluation of potential novel therapy approaches for OSCC that increase immunogenicity and overcome ICI resistance.