Nature Biomedical Engineering | Nanobody–STING Agonist Conjugates Based on Albumin Hitchhiking Enhance Cancer Immunotherapy

This study develops a modular nanobody drug delivery system that significantly prolongs circulation time and enhances tumor accumulation by conjugating STING agonists to anti-albumin nanobodies. This activates the innate immune system and promotes NK and T cell infiltration. The method further integrates PD-L1 targeting structures to enhance anti-tumor immune responses, offering broad clinical potential.

 

Literature Overview
The paper "Potentiating cancer immunotherapies with modular albumin-hitchhiking nanobody–STING agonist conjugates", published in Nature Biomedical Engineering, reviews and summarizes a novel cancer immunotherapy strategy. By constructing conjugates of anti-albumin nanobodies with STING agonists, the study overcomes limitations of traditional STING agonists, including poor pharmacokinetics and insufficient tumor targeting during systemic administration. The research further introduces PD-L1 targeting structures to create dual-functional nanobody-STING conjugates, enhancing anti-tumor immune responses and modulating immunosuppressive tumor microenvironments.

Background Knowledge
Recent advances in cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, have significantly improved survival rates for some patients. However, only about 15% of patients respond effectively to ICIs, primarily due to low tumor immunogenicity and strong immunosuppressive tumor microenvironments (TME). STING agonists, as key molecules for activating the innate immune system, promote type I interferons, inflammatory cytokines, and chemokines to enhance T cell activation and infiltration, transforming "cold" tumors into "hot" tumors. Traditional STING agonists like cyclic dinucleotides (CDNs), however, face clinical limitations due to poor pharmacokinetics and insufficient tumor accumulation during systemic administration. Therefore, developing a drug delivery platform that prolongs circulation time, improves tumor targeting, and enhances immune activation is critical. This study leverages the "hitchhiking" strategy of anti-albumin nanobodies to construct STING agonist conjugates, extending their half-life while introducing PD-L1 targeting modules through a modular design. This provides a novel solution for systemic cancer immunotherapy.

 

 

Research Methods and Experiments
Researchers first constructed high-affinity anti-albumin nanobodies (nAlb) and coupled STING agonists (diABZI) to nAlb via site-specific bioconjugation chemistry, forming the nAlb-diABZI conjugate. Subsequently, a bispecific nanobody strategy was employed to fuse anti-PD-L1 nanobodies with nAlb, creating bivalent nanobody–STING conjugates (AP-diABZI) that simultaneously target albumin and PD-L1. The therapeutic efficacy of these conjugates was validated in mouse tumor models through in vitro binding assays, pharmacokinetic analysis, tumor targeting assessment, and immune phenotyping.

Key Conclusions and Perspectives

• The STING agonist conjugated with anti-albumin nanobodies (nAlb-diABZI) significantly prolonged circulation time and enhanced tumor accumulation in mouse models, activating innate immune responses, promoting T and NK cell infiltration, and effectively suppressing tumor growth.
• The bispecific conjugate (AP-diABZI), constructed by fusing anti-PD-L1 nanobodies with anti-albumin nanobodies through modular design, not only improved tumor targeting but also activated adaptive immune responses by blocking PD-1/PD-L1 signaling.
• nAlb-diABZI demonstrated robust therapeutic efficacy across multiple tumor models, including serving as neoadjuvant therapy for adoptive T cell transfer, significantly prolonging survival and establishing long-term immune memory.
• In the PD-L1-high EMT6 breast cancer model, AP-diABZI showed superior anti-tumor efficacy and immune activation compared to single-target conjugates.
• The study revealed that nAlb-diABZI enters cells via endocytosis and releases active STING agonists in lysosomes, effectively activating downstream signaling pathways.

Research Significance and Prospects
This study provides a versatile, programmable drug delivery strategy for cancer immunotherapy. The albumin hitchhiking technology significantly improves pharmacokinetics and tumor targeting of STING agonists. The modular design allows further integration of multiple targeting modules, offering new insights into developing multispecific immunotherapies. Future applications could extend this strategy to other immune agonists, antibody-drug conjugates (ADCs), or CAR-T cell therapies, advancing personalized cancer immunotherapy.

 

 

Conclusion
This study introduces an innovative modular nanobody–STING agonist conjugate platform that leverages the anti-albumin nanobody's hitchhiking effect to significantly enhance STING agonist circulation time and tumor accumulation. The system activates innate immune cells while integrating PD-L1 targeting modules to block immunosuppressive signals, strengthening adaptive immune responses. This research establishes a new drug delivery paradigm for systemic cancer immunotherapy with broad application potential, particularly for refractory and low-immunogenicity tumors.

 

Blaise R Kimmel, Karan Arora, Neil C Chada, Justin M Balko, and John T Wilson. Potentiating cancer immunotherapies with modular albumin-hitchhiking nanobody–STING agonist conjugates. Nature Biomedical Engineering.