This study significantly improves tumor targeting and penetration through an erythrocyte membrane-camouflaged and iRGD peptide-modified engineered lactococcus system, effectively transforming cold tumors into hot tumors and enhancing the anti-tumor effects of PD-1 blockade therapy. This strategy not only improves the tumor microenvironment but also establishes systemic tumor-specific immune memory, offering new insights for treating drug-resistant solid tumors.
Literature Overview
This article, titled 'Intravenous iRGD-Guided, RBC-Membrane Camouflaged Lactococcus Lactis Remodels Cold NSCLC and Enhances PD-1 Blockade', was published in the journal Advanced Science. It reviews and summarizes the mechanisms of resistance to PD-1/PD-L1 blockade therapy in non-small cell lung cancer (NSCLC) and proposes a novel live bacterial therapeutic platform based on a biomimetic delivery system to overcome challenges such as low immunogenicity and insufficient T-cell infiltration.
Background Knowledge
PD-1/PD-L1 immune checkpoint inhibitors have significantly improved the prognosis for some NSCLC patients, yet the majority remain unresponsive due to limited tumor immunogenicity, impaired antigen presentation, and restricted infiltration of effector T cells. Live bacterial vaccines possess natural chemotaxis and pathogen-associated molecular patterns (PAMPs), making them effective as in situ vaccines for activating anti-tumor immunity. Building upon the existing FOLactis platform, this study introduces erythrocyte membrane camouflage combined with iRGD peptide modification to enhance systemic delivery capabilities, address the limitations of local injection, and improve deep tumor penetration and immune activation. The approach was validated in an orthotopic lung cancer model, with mechanisms explored through multiplex immune analyses, including dendritic cell expansion, CD8+ T cell activation, and reduction in immunosuppressive cells (e.g., Tregs), providing a novel therapeutic avenue for PD-1-resistant tumors.
Research Methods and Experiments
The study developed an iRGD-mRBC@FOLactis system by coating the FOLactis bacterial strain with an erythrocyte membrane and further modifying it with the iRGD peptide. The efficiency and membrane stability of the bacterial surface modifications were validated using flow cytometry, confocal microscopy, electron microscopy, and dynamic light scattering. The impact of iRGD modification on bacterial penetration was evaluated in a 3D tumor spheroid model. The anti-tumor efficacy of iRGD-mRBC@FOLactis in combination with PD-1 antibodies was tested in a murine orthotopic lung cancer model, incorporating bioluminescence imaging, histopathological analysis, flow cytometric detection of tumor-infiltrating immune cells, and cytokine profiling.
Key Conclusions and Perspectives
Research Significance and Prospects
This study presents a systemically deliverable live bacterial therapeutic platform that overcomes the limitations of traditional local injection strategies, offering a new immunomodulatory approach for PD-1-resistant NSCLC and other solid tumors. Future work will focus on optimizing membrane fusion efficiency and evaluating anti-tumor activity in multi-focal and metastatic models to facilitate clinical translation.
Conclusion
In summary, this study successfully developed a novel intravenously deliverable biomimetic therapeutic system, iRGD-mRBC@FOLactis, which leverages erythrocyte membrane camouflage and iRGD-mediated tumor penetration to significantly enhance infiltration and immune activation in cold tumors. When combined with PD-1 blockade, the system effectively reversed the immunologically cold phenotype of NSCLC, promoting effector T cell infiltration and suppressing immunosuppressive cell populations, thereby generating robust anti-tumor immune responses. This platform provides a broadly applicable strategy for treating PD-1-resistant solid tumors and holds promise for future applications across multiple cancer immunotherapy domains.
