PROJECT SUMMARY Immunotherapy has become an effective treatment option for certain types of cancers but has failed to generate significant clinical responses particularly in female patients with solid malignancies. Recently, multiple studies have identified sex differences in cancer immunotherapy efficacy, with males receiving the greater clinical benefit. Therefore, there is an urgent need to develop new therapeutic modalities for the prevention and treatment of solid malignancies while assessing sex differences in treatment efficacy. In support of this goal, we have recently developed a liposome delivery system (C3-liposomes) that utilizes complement C3 to specifically target antigen presenting cells (APCs). Our preliminary results show that C3- liposome delivery of activating compounds and tumor antigen to APCs leads to T cell activation and regression of tumors in murine cancer models. Our overall goal is to enhance activation and tumor antigen presentation using targeted C3-liposome delivery and examine sex differences in prophylactic immune response and treatment efficacy. Objective: This proposal will test the hypotheses that targeted C3-liposome delivery of a tumor antigen, mucin-1 (MUC1) in combination with therapeutic reprograming and activation of APCs prevents the development, progression, and recurrence of cancer. Specific Aim 1: Examine sex differences in C3- liposome prophylactic and therapeutic efficacy using a MUC1 transgenic mouse model. Study Design: Using the C3-liposome targeted delivery system, we will deliver the tumor associated antigen, MUC1, with therapeutics that reprogram and activate APCs in healthy and tumor bearing transgenic MUC1 mouse models of cancer. To improve immunogenicity, we will evaluate whether mice treated with MUC1 C3-liposomes develop a humoral antibody response and effector and memory T cell response against MUC1. To determine C3-liposome cancer vaccine efficacy, we will test whether MUC1 C3-liposome vaccination prevents the formation of tumors when used prophylactically and eliminates tumors when treated therapeutically in combination with checkpoint inhibitors. Sex differences in prophylactic immune response and C3-liposome treatment efficacy will be examined. Impact: It’s anticipated that our findings from this study will advance our knowledge of the immunotherapeutic approach of targeted drug and antigen delivery to APCs. This study also has the potential to elucidate sex difference in immune response and therapeutic efficacy of a novel nanoparticle vaccine and immunotherapy.