An in vivo MAIT cell activation and rejuvenation system for 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, liver-targeted nanoparticle platform designed for sustained in vivo delivery of the MR1-restricted MAIT agonist 5-OP-RU together with human IL-15. Ex vivo, MARS robustly expanded and activated MAIT cells from liver cancer patient peripheral blood and tumor tissues, enhancing effector cytokine production and cytotoxicity while limiting exhaustion. In vivo, MARS preferentially accumulated in the liver and induced durable MAIT cell activation, expansion, and potent tumor killing in human liver cancer xenograft models. Importantly, in a human myeloid cell–engrafted mouse model that recapitulates an immunosuppressive liver tumor microenvironment, MARS enabled MAIT cells to simultaneously eliminate liver tumor cells and MR1⁺ tumor-associated myeloid cells, resulting in effective tumor control and prolonged survival. Collectively, these findings establish MARS as a safe and effective in vivo MAIT cell engineering strategy that overcomes microenvironment-driven resistance and provides a promising immunotherapeutic approach for liver cancer.