Abstract 4316: An <i>in vivo</i> MAIT cell activation and rejuvenation systemfor liver cancer therapy

Abstract Mucosal-associated invariant T (MAIT) cells are liver-enriched unconventional T cells with potent antitumor potential, yet in liver cancer they are numerically reduced and functionally exhausted, limiting their therapeutic efficacy. To overcome these limitations, we developed a MAIT cell activation and rejuvenation system (MARS), a biomimetic scaffold engineered to deliver MAIT agonist 5-OP-RU and IL-15 directly to the liver, promoting MAIT cell activation, rejuvenation, and cytotoxic function. Ex vivo, MARS significantly stimulated MAIT cells from liver cancer patient peripheral blood and liver tissues, enhancing their effector function and cytotoxicity while reducing exhaustion. In vivo, MARS efficiently localized to the liver, boosting MAIT cell activation, expansion, and tumor-killing capacity in human liver cancer xenograft mouse models. Importantly, in a human myeloid cell-engrafted mouse model, MARS facilitated the depletion of liver MR1+ tumor-associated macrophages, further supporting MAIT cell antitumor activity. Collectively, through its biomimetic design and liver-targeted immunomodulatory effects, MARS provides an efficient and safe strategy to enhance MAIT cell-based immunotherapy for liver cancer. Citation Format: Yan-Ruide Li, Haochen Nan, Zhengyao Shao, Xinyuan Shen, Lili Yang. An in vivo MAIT cell activation and rejuvenation systemfor liver cancer 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 4316.