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Intravenous iRGD-Guided, RBC-Membrane Camouflaged Lactococcus Lactis Remodels Cold NSCLC and Enhances PD-1 Blockade
1Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
Abstract:
Resistance to programmed-death-1/programmed-death-ligand-1 (PD-1/PD-L1) blockade in non-small-cell lung cancer (NSCLC) arises mainly from weak tumor immunogenicity and limited effector T-cell infiltration. Here, this work presents an intravenously deliverable "living medicine" that addresses these barriers through biomimetic cloaking, tumor-penetrating guidance, and synthetic-biology-driven cytokine release. Lactococcus lactis is engineered to co-secrete Flt3L and OX40L (FOLactis) and then camouflage with red-blood-cell membranes, producing long-circulating mRBC@FOLactis. Conjugation of the iRGD peptide (iRGD-mRBC@FOLactis) enables trans-endothelial migration and deep (≥200 µm) interstitial penetration, yielding a fourfold increase in intratumorally bacterial accumulation versus unmodified FOLactis. In the orthotopic Lewis lung carcinoma (LLC) model, a single intravenous dose of iRGD-mRBC@FOLactis combined with anti-PD-1 antibody achieves complete tumor regression in 60% of mice, doubles median survival (p < 0.001), and generates systemic tumor-specific immune memory. Mechanistically, local Flt3L and OX40L secretion expands cross-presenting dendritic cells (DCs), boosts CD8⁺ T-cell priming, and converts immunologically "cold" tumors into inflamed, T-cell-rich lesions, thereby overcoming primary resistance to checkpoint blockade. This multifunctional probiotic platform establishes a generalizable strategy for systemic delivery of living therapeutics and offers a powerful adjunct to PD-1/PD-L1 blockade for NSCLC and other treatment-resistant solid tumors.
Insights
Engineered bacteria overcome resistance to checkpoint blockade therapy in lung cancer by enhancing anti-tumor immunity. This living medicine strategy boosts T-cell infiltration and converts cold tumors into inflamed lesions, improving survival rates.
Area of Science:
- Oncology
- Immunotherapy
- Synthetic Biology
Background:
- Resistance to programmed-death-1/programmed-death-ligand-1 (PD-1/PD-L1) blockade in non-small-cell lung cancer (NSCLC) is a significant clinical challenge.
- This resistance is often due to weak tumor immunogenicity and insufficient effector T-cell infiltration.
Purpose of the Study:
- To develop an intravenously deliverable "living medicine" to overcome primary resistance to PD-1/PD-L1 blockade in NSCLC.
- To engineer Lactococcus lactis to enhance tumor immunogenicity and T-cell infiltration.
Main Methods:
- Engineered Lactococcus lactis to co-secrete Flt3L and OX40L (FOLactis).
- Camouflaged engineered bacteria with red-blood-cell membranes (mRBC@FOLactis) for long circulation.
- Conjugated iRGD peptide for enhanced tumor penetration (iRGD-mRBC@FOLactis).
- Administered iRGD-mRBC@FOLactis in combination with anti-PD-1 antibody in an orthotopic Lewis lung carcinoma (LLC) model.
Main Results:
- iRGD-mRBC@FOLactis showed a fourfold increase in intratumoral accumulation compared to unmodified FOLactis.
- A single dose of iRGD-mRBC@FOLactis plus anti-PD-1 achieved complete tumor regression in 60% of mice and doubled median survival.
- The treatment expanded cross-presenting dendritic cells, boosted CD8+ T-cell priming, and converted "cold" tumors into inflamed, T-cell-rich lesions.
Conclusions:
- This multifunctional probiotic platform effectively overcomes primary resistance to PD-1/PD-L1 blockade in NSCLC.
- The strategy establishes a generalizable approach for systemic delivery of living therapeutics.
- This approach offers a powerful adjunct for treating NSCLC and other solid tumors resistant to current immunotherapies.
