Abstract Lung squamous cell carcinoma (LUSC) represents 30% of non-small cell lung cancer (NSCLC) cases and has a high mortality rate with limited targeted therapies. Unlike lung adenocarcinoma (LUAD), which has seen advancements in targeted therapies, LUSC has not benefited from similar breakthroughs despite having similar genetic abnormalities. While immune checkpoint inhibitor therapies have shown promise in some LUSC patients, a significant portion does not respond effectively, leaving limited treatment options. The metabolic landscape of tumors plays a crucial role in shaping the efficacy of immunotherapies, especially adoptive T cell therapies. However, identifying actionable metabolic vulnerabilities involved in T cell therapy is poorly understood. Here, we performed a high-throughput CRISPR-Cas9 screen targeting metabolic genes in an orthotopic LUSC mouse model to identify key metabolic enzymes that would sensitize the tumors to adoptive CD8+ T cell therapy. By comparing sgRNA enrichment and depletion between tumors treated with adoptive T cells and those receiving PBS, we identified genes that are involved in the fatty acid biosynthesis pathway as potential suppressors of T cell-mediated killing in this tumor model. Moreover, pilot experiments indicate that loss of these genes promote invitro cytotoxic killing when tumor cells were co-cultured with T cells. Additionally, in vivo studies showed a decrease in tumor growth. Experiments are underway to evaluate the effect of adoptive T cell therapy in vivo. Citation Format: Verra Ngwa, Jin Chen. Using functional CRISPR screening to investigate metabolic genes in lung squamous cell carcinoma adoptive T cell therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4915.
Ngwa et al. (2026) studied this question.