From fermentation to pharmabiotics: engineering kefir-derived Lactobacillus for targeted intratumoral immunotherapy...

Colorectal cancer (CRC) is a leading cause of cancer-related death, and most patients benefit little from immune checkpoint inhibitors (ICIs) because microsatellite-stable (MSS) tumors are largely resistant to them. In this context, this review aims to address a fermentation-to-pharmabiotic pipeline to convert Lactobacillus strains in kefir into engineered Live Biotherapeutic Products (LBPs). Scientists have discovered an effective way to isolate beneficial bacteria from kefir, which can be used to develop new medical treatments through laboratory-controlled engineered LBP. With synthetic biology, bacteria can be engineered to specifically target hypoxic tumor regions and serve as in situ bioreactors and release potent payloads such as nanobodies and cytokines. This local therapeutic intervention is capable of remodeling the immunosuppressive microenvironment, which, in effect, turns cold, resistant tumors into hot, T-cell-inflamed targets to systemic immunotherapy. The paper examines the shift to precision medicine in place of probiotics, with preclinical indications of synergy with ICIs, and the difficult-to-clear translational challenges, such as biocontainment, production, and regulation.