Intravenous iRGD‐Guided, RBC‐Membrane Camouflaged Lactococcus Lactis Remodels Cold NSCLC and Enhances PD‐1 Blockade

TL;DR

A new probiotic treatment improves lung cancer response to immunotherapy by boosting immune cell activity and targeting resistant tumors.

Contribution

A novel probiotic platform using biomimetic cloaking and tumor-penetrating peptides enhances PD-1 blockade efficacy in cold tumors.

Findings

iRGD-mRBC@FOLactis achieves fourfold higher tumor accumulation compared to unmodified bacteria.

The treatment combined with anti-PD-1 antibody causes complete tumor regression in 60% of mice.

The platform converts cold tumors into inflamed, T-cell-rich lesions, improving checkpoint blockade effectiveness.

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.

This study presents an engineered probiotic platform, iRGD‐mRBC@FOLactis, combining red blood cell membrane cloaking and tumor‐penetrating peptide iRGD for enhanced PD‐1 blockade. The platform improves tumor targeting, immune cell activation and therapeutic efficacy in lung cancer, demonstrating significant promise in overcoming PD‐1/PD‐L1 therapy resistance. Created with BioRender.com.

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