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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • Weibin Zou,
  • Linbing Zou,
  • Wei Guo

摘要

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.