Reprogrammed Mesenchymal Stem Cells for Targeted Delivery of Chemoimmunotherapeutics in Gastric Cancer

Authors
Jun Yung WOO^1,2,§, Vivien KOH^3,4,§, Yoon Khei HO^1,2, Bok Yan Jimmy SO^3,5, Yana ZAVROS⁶, Heng-Phon TOO^1,2, Wei Peng YONG^3,4

§ Equal contribution

Affiliations

1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
2. NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore
3. National University Cancer Institute Singapore, National University Health System
4. Cancer Science Institute of Singapore, National University of Singapore
5. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore
6. Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona

Abstract
The emergence of cell and gene therapy has opened up exciting new possibilities for treating therapy-resistant cancers. Among these therapies, mesenchymal stem cells (MSCs) stand out as promising tools due to their natural ability to home in on tumours. These MSCs act as specialised bio-factories, releasing therapeutic proteins directly at the tumour site while sparing healthy tissues from systemic toxicity. Using a genemodified MSC-directed chemoimmunotherapy approach to enhance cGAS-STINGInterferon signalling, we aim to achieve a potent anti-tumour effect while activating the adaptive immune system. In a gastric cancer patient-derived organoid (PDO) model, we observed effective MSC homing and a strong anti-tumour response. Noteworthy, our preliminary data from an MSC-PDO-cytotoxic T lymphocyte co-culture system suggest enhanced tumour cell killing when combining therapeutic MSCs with immune checkpoint inhibitors. Ongoing research will delve into the underlying mechanisms and explore the immune benefits of this innovative treatment strategy.