Oral probiotics microgel plus Galunisertib reduced TGF-β blockade resistance and enhanced anti-tumor immune responses in colorectal cancer

Transforming growth factor β (TGF-β), a versatile immunosuppressive cytokine, has gained increasing attention as a potential target for cancer immunotherapy. However, current strategies are constrained by tumor heterogeneity and drug resistance. Therapeutic probiotics, such as Escherichia coli Nissle1917 ( EcN ), not only regulate the gut microbiota to increase beneficial bacteria with anti-tumor effects, but also modulate immune factors within the body, thereby enhancing immunity. In this study, we developed an oral microgel delivery system of EcN @(CS-SA) 2 by electrostatic interaction between chitosan (CS) and sodium alginate (SA), aiming to enhance its bioavailability in the gastrointestinal tract (GIT). Notably, EcN @(CS-SA) 2 microgel showed a synergistic enhancement of the anti-tumor efficacy of Galunisertib (Gal, a TGF-β inhibitor) by inducing apoptosis and immunogenic cell death (ICD) in tumor cells, as well as promoting increased infiltration of CD8 + T cells into the tumor microenvironment (TME).