MSCs delivering LIGHT prime immune response against CAFs to harness antigen loss variants

The tumor niche promotes immune tolerance, enabling malignant cells to evade surveillance. Mesenchymal stem cells (MSCs) have multipotential differentiation capacity and provide a niche for bone marrow homeostasis. MSCs home to tumor tissues, where they can differentiate into Cancer-associated fibroblasts (CAFs). Within the tumor microenvironment, MSCs drive tumor progression by fostering immune suppression, secreting pro-tumorigenic cytokines, and, in some contexts, maintaining dormancy for later relapse. In this study, we engineered MSCs to deliver the immuno-stimulatory TNF superfamily ligand LIGHT (MSC-L). We found that MSC-L simultaneously primed immune responses against both tumor cells and CAFs. This effect relies on the LIGHT-mediated activation of naïve T cells in draining lymph nodes, which subsequently infiltrate the tumor. The recruited T cells eradicate CAFs, thereby remodeling the immunosuppressive niche and harnessing otherwise immune tolerance antigen loss variants. Our findings underscore the critical role of niche reprogramming in tumor control and demonstrate a novel strategy for co-targeting tumor cells and CAFs, even in immune resistant settings. This approach provides a promising foundation for clinical translation.