Introduction: Emerging evidence supports the presence of distinct intratumoral microbiota in several solid malignancies, including liver and pancreatic cancers. These tumor-associated microbial communities contribute to cancer progression, chemoresistance, and genomic instability through induction of oncogenic metabolites and inflammation. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that sense microbial metabolic imbalances, and altered MAIT cell biodistribution and functional impairments are commonly observed in gastrointestinal cancer patients.

Methods: We developed a robust ex vivo methodology to generate clinically relevant quantities of human MAIT cells from peripheral blood. These expanded cells exhibit an activated phenotype, cytolytic potential, and enhanced tissue-targeting capabilities. Their functionality as a cancer immunotherapy against solid tumors was evaluated using liver- and pancreatic tumor spheroids.

Results: When engineered to express a T-cell receptor (TCR) specific for the hepatotropic oncovirus HBV, MAIT cells acquired novel antigen specificity and the specific polyfunctionality, while retaining their antimicrobial activity against pathogenic bacteria. Notably, their tumor-homing ability to HBV-associated hepatocellular carcinoma mirrors that of conventional T cells currently used in clinical practice. Furthermore, MAIT cells responded robustly to bacteria isolated from patient-derived pancreatic tumors via activation of 5-OP-RU–specific TCRs. Under hypoxic conditions mimicking the tumor microenvironment, MAIT cells were activated by both experimental infection and bacterial secretomes, leading to a reduction in intratumoral bacterial load within the tumor spheroids. These results highlight a dual function for ex vivo expanded MAIT cells in targeting both tumor-associated bacteria and oncogenic viruses.

Conclusion: Our findings highlight the potential of ex vivo expanded MAIT cells in targeting cancers associated with microbial dysregulation and pave the way for microbiota-targeted immunotherapies.

References

Gaiser et al. Gut 2019

Parrot et al., JCI Insight 2021

Healy K et al., JHep Rep 2021

Halimi et al. Gut Microbes 2021

Li, Yan-Ruide et al. Mol Ther 2023

Cao et al. Sig Transduct Target Ther 2024

Poojabahen et al. Front Immunol 2025