This study developed a bioorthogonal metabolic engineering-based Biordee strategy that leverages IgG Fc modifications to enhance macrophage-mediated phagocytosis, effectively suppressing chemotherapy-induced tumor exosome release. The approach strengthens anti-tumor immune responses and inhibits breast cancer liver metastasis, offering novel insights for cancer immunotherapy.
Literature Overview
Published in Advanced Science, this study titled 'Enhancing Chemotherapy-Related Immune Responses via Bioorthogonal Metabolic Engineering-Driven Tumor Exosomes Elimination' reviews a novel exosome clearance strategy called Biordee. It systematically evaluates the strategy's efficacy in mouse models, demonstrating significant suppression of chemotherapy-induced exosome release, activation of T-cell immune responses, and inhibition of tumor metastasis.
Background Knowledge
Tumor-derived exosomes (TExo) play critical roles in tumor microenvironment regulation, immune escape, and pre-metastatic niche formation. Exosomal PD-L1 particularly contributes to CD8+ T cell functional exhaustion, suppressing systemic anti-tumor immunity. While chemotherapy remains a first-line treatment, it paradoxically induces TExo release that promotes metastasis. Developing efficient TExo clearance strategies is essential for improving chemotherapy outcomes. Current approaches include pharmacological inhibition of exosome biogenesis and nanomaterial-based adsorption, but these face limitations in targeting efficiency and clinical feasibility. This study introduces the Biordee strategy, combining glycometabolic engineering with bioorthogonal reactions: tumor cell membranes are modified to express azide groups (N3), enabling exosome labeling and subsequent capture by DBCO-modified IgG Fc through specific macrophage recognition. The method effectively suppressed chemotherapy-induced breast cancer liver metastasis in mouse models while enhancing immunotherapy, establishing a new bioengineered pathway for cancer treatment.
Research Methods and Experiments
The research team first developed a mannose-N3@liposome (Man@Lip) delivery system to label tumor cell membranes with azide groups (N3) through glycometabolic engineering. This modification enabled tumor cells to secrete N3-labeled exosomes (TExo-N3). Subsequently, DBCO-modified IgG Fc was employed to bind TExo-N3 via bioorthogonal reaction, forming TExo-Fc complexes. Flow cytometry, confocal microscopy, and ELISA were used to evaluate the binding efficiency between TExo-Fc and macrophages. The anti-tumor efficacy of combining chemotherapy with Biordee was assessed in mouse models of breast cancer, focusing on tumor growth, immune microenvironment modulation, and metastasis inhibition.
Key Conclusions and Perspectives
Research Significance and Prospects
This study introduces a novel exosome clearance mechanism through bioorthogonal reactions that enhance macrophage phagocytosis, effectively mitigating chemotherapy-induced immune suppression. Future work will focus on long-term toxicity evaluation, optimization of TExo targeting specificity, and expansion to other tumor models. The approach provides theoretical support for exosome engineering and immunomodulation, with potential combination with immune checkpoint inhibitors to improve cancer immunotherapy efficacy.
Conclusion
This study pioneers the application of bioorthogonal metabolic engineering for exosome clearance by constructing TExo-Fc complexes, enabling remodeling of the post-chemotherapy immune microenvironment. The Biordee strategy effectively suppresses breast cancer liver metastasis while enhancing systemic anti-tumor immunity. Demonstrating excellent biocompatibility and safety, this method establishes a novel bioengineering tool for cancer immunotherapy. Future optimization of targeting specificity and application to other cancers or chronic diseases will further advance clinical translation.
