Lactobacillus reuteri Assists Engineered Bacteria That Target Tumors to Release PD-L1nb to Mitigate the Adverse Effects of Breast Cancer Immunotherapy

Programmed death protein-ligand 1 (PD-L1) inhibitors demonstrate significant antitumor efficacy by modulating T-cell activity and inhibiting the PD-1/PD-L1 pathway, thus enhancing immune responses. Despite their robust effects, systemic administration of these inhibitors is linked to severe immune toxicity. To address this issue, we engineered a strain, REP, which releases PD-L1 nanoantibodies (PD-L1nb) to treat breast cancer and attenuate immunotherapy-related side effects. REP selectively targets tumors and periodically releases PD-L1nb within tumors via a quorum-sensing lysis system. Administration of 10⁸ colony-forming units (CFU) of REP led to a substantial 52% reduction in tumor growth, achieved through the sustained release of PD-L1nb. Importantly, there were no detectable lesions in other organs, with the exception of mild intestinal damage. Further, we explored the potential of a combined treatment using Lactobacillus reuteri (LR) and REP to alleviate intestinal inflammation. LR modulates the expression of inflammatory markers IL-1β, IL-6, and IL-10 through the JNK pathway, reducing intestinal inflammation without compromising REP's antitumor efficacy. Consequently, we formulated a dual strategy employing an engineered strain and probiotics to reduce the adverse effects of immunotherapy in cancer treatment.