ABSTRACT This proposal is being submitted in response to PA-23-189 to support minority graduate student Anastasia Abello. She is conducting work closely related to Dr. Xiao-Jing Wang’s project 2 of the CO HNC SPORE CA261605 Head and Neck Squamous Cell Carcinoma (HNSCC) is associated with significant morbidity and mortality, with immune checkpoint inhibitors (ICIs) showing limited efficacy. Emerging evidence suggests the potential impact of altered microbiomes on cancer progression and immunotherapy response. Additionally, bacteria have been detected inside tumors, including HNSCC. Recent studies suggest a crucial role of the oral microbiome in modulating the efficacy of ICIs. Moreover, environmental factors, particularly diet, have been linked to microbiome alterations and impaired immunotherapy response. I propose to use preclinical mouse models, human clinical specimens, and multiple omics techniques to identify the mechanisms through which the oral microbiome influences cancer progression and immunotherapeutic responses. This research aligns with the parental SPORE project of improving immunotherapy, yet brings new studies addressing microbiome effects on cancer therapeutics and holds promise for improving patient quality of life through better treatment outcome. Overall, the goal of this proposal is to leverage unique murine models and human patient samples to advance our understanding of the role of the oral microbiome in HNSCC and enhance therapeutic approaches. The hypothesis of this proposal is that alterations to the oral microbiome through diet significantly impact immunotherapeutic response in HNSCC via the mechanisms of direct interactions between microbiomes, tumor cells, the microenvironment, and indirectly by inducing metabolic changes to the host and microbial metabolites. Aim 1 will examine the effects of changes in the oral microbiome from a Western diet (WD) and on tumor growth of mouse HNSCC models. Aim 2 will assess the role of the oral microbiome on immunotherapy response upon changes from a WD in HNSCC mouse models. Additionally, this aim will examine if there are differences in oral microbiomes of human HNSCC patients between immunotherapeutic responder (R) and non-responder (NR). Aim 3 will identify spatial and systemic predictive marker candidates of immunotherapy response affected by dietary-associated microbiomes in mouse HNSCC models and human specimens. This study will provide insight into the interplay between the oral microbiome, diet, cancer progression, and immunotherapy response. It will also identify predictive biomarkers linked to altered microbiomes in HNSCC.