Abstract 6325: Zeaxanthin augments CD8+ effector T cell function by enhancing TCR stimulation

Abstract The evolution of diet has played an essential role in shaping human physiology and pathology, including the development of the immune system and responses to environmental stimuli. However, the specific mechanisms underlying the regulatory significance of dietary components in modulating anti-tumor immunity remain largely unknown. Here, we applied a co-culture screen approach using a blood nutrient compound library to identify zeaxanthin, a dietary carotenoid pigment found in many fruits and vegetables that is important for eye health, as an immunomodulator that enhances cytotoxicity of CD8+ T cells against tumor cells. Oral zeaxanthin, but not lutein, a zeaxanthin structural isomer, enhances anti-tumor immunity in vivo. Integrated multi-omics mechanistic studies reveal that zeaxanthin directly promotes T-cell receptor (TCR) stimulation on CD8+ T cell surface, leading to improved intracellular TCR signaling for effector T cell function. Hence, zeaxanthin treatment augments effectiveness of immune checkpoint inhibitor in vivo and human TCR-engineered CD8+ T cells to induce cell death against co-cultured tumor cells. Our findings uncover a previously unknown immunoregulatory function of zeaxanthin, which has translational potential as a dietary element in bolstering immunotherapy. Citation Format: Freya Q. Zhang, Jiacheng Li, Rukang Zhang, Jiayi Tu, Zhicheng Xie, Takemasa Tsuji, Hardik Shah, Matthew O. Ross, Ruitu Lyu, Junko Matsuzaki, Kelly Xue, Fatima Choudhry, Chunzhao Yin, Hamed R. Youshanlouei, Syed Shah, Michael W. Drazer, Marc Bissonnette, Yuancheng Li, Hui Mao, Jun Huang, Lei Dong, Rui Su, Chuan He, Kunle Odunsi, Jing Chen, Hao Fan. Zeaxanthin augments CD8+ effector T cell function by enhancing TCR stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6325.