Abstract Mesenchymal stromal cells (MSCs) derived from bone marrow (BM-MSCs) exhibit inherent tumor-tropic behavior (Andreeff M., Cancer Res. 2002, JNCI 2004). However, their finite proliferative lifespan, donor-to-donor variability, and senescence-associated transcriptional drift present barriers to clinical scalability. To address these limitations, we reprogrammed adult dermal fibroblasts into induced pluripotent stem cells (iPSCs) using a synthetic, non-integrating mRNA transfection system. These iPSCs were stably modified to express interleukin-7 and interleukin-15, prior to mesodermal lineage specification into MSCs (hereafter referred to as IL7-IL15-iMSCs). Flow cytometry and transcriptomic profiling confirmed expression of canonical MSC markers (CD73+CD90+CD105+), absence of hematopoietic or endothelial lineage antigens and trilineage differentiation potential. IL7-IL15-iMSCs secreted supraphysiologic levels of cytokines, converting immune-suppressive MSCs into immune-activating MSCs. In vitro, IL7-IL15-iMSCs induced potent T cell proliferation sustaining the long-term expansion of T cells, macrophages and CAR T cells in vitro, and induced tumor cell death in a triple co-culture system comprising IL7-IL15-iMSCs, the ovarian cancer cell line ID8, and human PBMCs. In a syngeneic mouse model of ovarian cancer (ID8 and platinum-resistant ID8 cells in C57BL/6 mice), intraperitoneal administration of IL7-IL15-MSCs resulted in reduced tumor burden and extended survival. Immunohistochemical and CyTOF analyses revealed massive infiltration of activated T cells, macrophages, and other immune cells into the tumor microenvironment (TME) as well as enrichment in tumoricidal M1-type macrophages, with no detection of exhausted or regulatory T cells, in contrast to controls. To mitigate pulmonary first-pass entrapment associated with systemic, intra-venous (IV) MSC delivery, we optimized a fractionated low-dose IV administration regimen in the orthotopic 4T1 triple-negative breast cancer model. Six weeks post IL7-IL15-iMSC IV administration, tissue IHC staining showed robust iMSC localization to the TME, infiltration of immune cells and tumor reduction as observed in ovarian cancer. Conclusion: These data establish IL7-IL15-iMSCs as a novel, immunologically active stromal cell platform capable of remodeling the TME and amplifying both innate and adaptive anti-tumor responses. IL7-IL15 iMSC convert an immune-suppressed into an immune-activated TME in diverse tumor types. The scalability of iPSC-derived MSCs, combined with synthetic mRNA reprogramming and stable cytokine expression, supports the suitability of this platform for clinical translation. A first clinical trial in ovarian cancer is under development. Citation Format: Michael Andreeff, Sandeep Singh, Andrea Bedoy, Muharrem Muftuoglu, Li Li, Vivek Anand, Dipmoy Nath, Lauren Ostermann, Ivo Vletic, Christopher D. Pacheco, Mahesh Basyal, Taeyun Kim, Kyle M. Garland, Matthew Angel, Sanjeev Luther, Robert Pierce, Christopher B. Rohde. Engineered IL7/IL15 secreting iPSC-derived mesenchymal stromal cells convert the immunosuppressive into immune-activated tumor microenvironments (TME) and potentiate antitumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7953.
Andreeff et al. (Fri,) studied this question.