Nature Communications | Targeted Regulation of Tumor Collagen Fibers Enhances Lung Cancer Immunotherapy

This study developed an inhalable lipid nanoparticle (LNP) delivery system that simultaneously targets collagen-regulating receptor DDR1 and immune checkpoint PD-L1. It effectively improves the immune-excluded and immunosuppressive tumor microenvironment, offering an innovative strategy for lung cancer immunotherapy.

 

Literature Overview
This paper, "Modulating tumor collagen fiber alignment for enhanced lung cancer immunotherapy via inhaled RNA" published in Nature Communications, reviews innovative approaches to modulate collagen fiber alignment and PD-L1 expression through inhaled RNA strategies to improve the lung cancer immune microenvironment. The article details the LNP system's efficient pulmonary delivery capabilities and its dual regulatory effects on tumor microenvironment through in vitro and in vivo experiments, ultimately achieving significant enhancement of anti-tumor immune responses.

Background Knowledge
Lung cancer, one of the deadliest malignancies globally, has long faced physical and immune barriers limiting immunotherapy efficacy. Highly ordered collagen fibers in the tumor microenvironment (TME) form physical barriers impeding T cell infiltration, while high PD-L1 expression on tumor cells further suppresses T cell activity, enabling immune evasion. Although immune checkpoint blockade (ICB) therapy has shown limited success in melanoma and non-small cell lung cancer, efficacy remains constrained in various solid tumors due to insufficient T cell infiltration and immunosuppressive microenvironments. This study addresses these challenges through a dual-targeting strategy against collagen architecture and PD-L1 signaling, establishing a breakthrough approach for solid tumor immunotherapy. The designed inhalable LNP system co-delivers mRNA encoding anti-DDR1 single-chain antibody fragments (scFv) and PD-L1-targeting siRNA, blocking DDR1-collagen interactions and silencing PD-L1 expression to overcome immune exclusion and suppression in lung cancer treatment.

 

 

Research Methods and Experiments
The research team developed an inhalable lipid nanoparticle (LNP) system for co-delivering mRNA-encoded anti-DDR1 single-chain variable fragments (mscFv) and PD-L1-targeting siRNA (siPD-L1) to pulmonary tumor cells. The therapeutic effects across different treatment modalities on tumor microenvironment were evaluated in C57BL/6 mouse models, focusing on collagen fiber alignment, T cell infiltration, and immune checkpoint regulation.

Key Conclusions and Perspectives

• The inhalable LNP system maintains stable physicochemical properties before and after nebulization, including particle size, polydispersity index (PDI), and encapsulation efficiency, with high cellular uptake and gene expression levels.
• mscFv@LNP effectively disrupts collagen fiber alignment by blocking DDR1-collagen interactions, reducing tumor stiffness to facilitate T cell infiltration.
• siPD-L1 achieves PD-L1 gene silencing, alleviating T cell suppression and enhancing anti-tumor activity.
• In both orthotopic and metastatic lung cancer models, mscFv/siPD-L1@LNP inhalation significantly suppresses tumor growth, extends survival duration, and demonstrates negligible toxicity.
• The strategy enhances T cell-mediated tumor cytotoxicity while increasing IFN-γ and TNF-α secretion, simultaneously reducing immunosuppressive cell infiltration (Treg and MDSC).

Research Significance and Prospects
This study provides a novel combinatorial strategy for lung cancer and other solid tumor immunotherapies, overcoming dual barriers of restricted T cell infiltration and immunosuppression. Future optimizations may focus on improving mRNA/siRNA stability and expression efficiency within the LNP system, while exploring its applicability across additional tumor models. The platform also demonstrates potential for combination therapies with CAR-T cell approaches and cancer vaccines, establishing a foundation for personalized immunotherapy applications.

 

 

Conclusion
This innovative inhalable LNP system enables dual regulation of collagen architecture and PD-L1 immune checkpoints within the lung tumor microenvironment, substantially enhancing anti-tumor immune responses. Demonstrating significant tumor suppression and survival extension in animal models, this strategy offers a scalable solution for solid tumor immunotherapy. The findings emphasize that simultaneous intervention against physical barriers and immunosuppressive mechanisms is critical for improving immunotherapy response rates. With localized high-efficiency delivery and systemic immune activation, this platform exhibits strong translational potential for clinical development. Further optimization could extend applications to other cancers, including breast cancer lung metastasis models.

 

Bin Hu, William Stewart, Qijing Chen, Xiaoyang Xu, and Xue-Qing Zhang. Modulating tumor collagen fiber alignment for enhanced lung cancer immunotherapy via inhaled RNA. Nature Communications.