An in vivo MAIT cell activation and rejuvenation systemfor liver cancer therapy

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.