SUMMARY Development of novel therapeutics targeting cellular and molecular mechanisms underlying health disparities is among the top priorities of Wake Forest Baptist Comprehensive Cancer Center (WFBCCC). Our thoracic oncologists have been actively treating lung cancer patients with immune checkpoint blockade (ICB) drugs with up to 30% efficacy in patients with non-small cell lung cancer (NSCLC). We found that Black lung cancer patients showed significantly better response to ICB than White patients, suggesting that disparities experienced by Black patients could be overcome with ICB. Given ICB-resistance over time, we posit that increased efficacy could be achieved through novel ICB and targeted combination therapies. Our preliminary single-cell RNA sequencing (scRNAseq) studies show more infiltrating exhausted CD8+ T cells and fewer myeloid and natural killer cells in NSCLC biopsies from Black compared to White patients. In tumors from Black patients, exhausted CD8+ T cells expressed high levels of CTLA-4 and CD137(4-1BB), suggesting a possible beneficial response to ICB by reversing the pool of exhausted T cells to restore anti-tumor function. Transcriptional pathway analysis of scRNAseq data also identified redox and lipid metabolism as top altered molecular changes. Based on these findings and published data showing redox- and lipid-mediated regulation of immune cell reprogramming, we propose two central hypotheses: (a) In Black NSCLC patients, unique features of redox and lipid metabolism give rise to dysfunctional immune cell ecosystems that underlie health disparities, and (b) these can be exploited by innovative redox and lipid metabolism-targeting therapeutics to further improve response to ICB. Lung cancer is the most frequent cancer diagnosis at WFBCCC. Among patients seen at our Cancer Center, 14% are Black, and epidemiologic data collected by our Office of Cancer Health Equity show that Black patients in our region have lung cancer incidence and mortality rates 15.1% and 15.5% higher, respectively, than rates among Black patients in the U.S. We are in a unique position to investigate the molecular events that lead to differences in ICB responses by Black lung cancer patients and to develop effective therapeutic strategies to overcome health disparities. We will achieve these goals through three Specific Aims: 1) To generate high-resolution spatial single-cell expression profiles of tumors and the tumor microenvironment in Black and White patients with NSCLC; 2) To generate supporting data linking specific genomic events in NSCLC from Black patients to reprogramming of redox and lipid metabolism; 3) To generate pre-clinical data demonstrating that targeting mitochondrial redox and lipid metabolism can reshape the tumor microenvironment and improve response to ICB. We will use NSCLC patient-derived organoids and cell lines in humanized mouse models to determine whether MCL1 inhibitors (AZD5991 or VU661013) and Devimistat (CPI-613) can...