Adoptive MAIT cell therapy for liver cancer enhanced by multimodal modulation of immune receptors and checkpoints.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that recognize riboflavin-derived metabolites presented by the monomorphic major histocompatibility complex (MHC)-class I-related molecule MR1. MAIT cells are highly enriched in the human liver and are increasingly implicated in liver cancer immunity, yet their antitumor potential and therapeutic applicability remain incompletely defined. METHODS: Here, we profiled MAIT cells derived from peripheral blood of healthy donors and patients with hepatocellular carcinoma, revealing disease-associated phenotypic alterations marked by immune checkpoint dysregulation. To address current therapeutic limitations, we developed a robust ex vivo expansion platform capable of generating MAIT cells with high yield, purity, and potent cytotoxic function. Using multiple human liver cancer subcutaneous and orthotopic xenograft mouse models, we demonstrate that adoptively transferred MAIT cells mediate effective tumor targeting and killing in vivo. FINDINGS: Mechanistically, MAIT cell antitumor activity is driven by both T cell receptor (TCR)-dependent recognition and natural killer receptor (NKR)-mediated cytotoxicity and is further enhanced by antigen stimulation; cytokine receptor signaling, particularly via interleukin (IL)-15; and immune checkpoint modulation involving programmed cell death protein 1 (PD-1) and T cell immunoglobulin and ITIM domain (TIGIT). In addition, MAIT cells demonstrated a favorable safety profile, with no evidence of liver toxicity observed in xenograft mouse models. CONCLUSIONS: Together, these findings establish MAIT cells as functional antitumor effectors in liver cancer and provide a mechanistic and translational framework for adoptive MAIT cell therapy enhanced by multimodal modulation of immune receptors and checkpoints. FUNDING: Major funding was provided by the California Institute for Regenerative Medicine (CIRM).