Stem cell-derived paracrine factors by modulated reactive oxygen species to enhance cancer immunotherapy

Herein, we present an approach for manipulating paracrine factors and signaling pathways in adipose-derived stem cells (ADSCs) to achieve highly effective tumor immunotherapy. Our method involves precise control of reactive oxygen species concentration using the CD90-maleimide-pluronic F68-chlorin e6 conjugate (CPFC) to create ACPFC, which is then attached to ADSCs through the CD90 receptor-specific interaction. By regulating the irradiated laser power, ACPFC promotes signaling pathways such as cascade-3, VEGFR2, α2β1, C3AR1, CR1-4, and C5AR1, leading to the secretion of various inflammatory cytokines such as IFN-γ, TGF-β, and IL-6, while inhibiting AKT, ERK, NFkB, PAR1, and PAR3/4 signaling pathways to reduce the secretion of cell growth factors like TIMP-1, TIMP-2, VEGF, Ang-2, FGF-2, and HGF. When ACPFC is injected intravenously into a tumor animal model, it autonomously targets and accumulates at the tumor site, and upon laser irradiation, it generates various anti-inflammatory factors while reducing angiogenesis growth factors. The resulting antitumor response recruits CD3⁺CD8⁺ cytotoxic T cells and CD3⁺CD4⁺ helper T cells into the tumor and spleen, leading to highly effective melanoma and pancreatic tumor treatment in mice. Our technology for regulating stem cell paracrine factors holds significant promise for the treatment of various diseases.