Mast cells: masters of targeted drug delivery

Lewen Mao; Ke Cheng

doi:10.15302/vita.2026.01.0007

Vita > Cutting Edge > DOI: 10.15302/vita.2026.01.0007

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Mast cells: masters of targeted drug delivery

Lewen Mao ,
Ke Cheng

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Engineered IgE-sensitized mast cells (IgE-MCs) could serve as an elegant and conceptually innovative platform for tumor-targeted oncolytic virus delivery, mediating tumor-specific targeting and synchronized immune activation within the tumor microenvironment (TME). In a recent study in Cell, Xu et al. demonstrate robust antitumor efficacy of IgE-MCs and shed further light on personalized immunotherapy and broadly adaptable delivery paradigms.

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Despite remarkable advances in cancer immunotherapy, effective drug delivery for solid tumors remains one of the most formidable challenges in biomedical engineering. While genetically engineered cell therapies, such as CAR-T cells and CAR-macrophages, have achieved transformative success, their clinical translation is constrained by complex manufacturing and safety considerations^1,2. Additionally, physical barriers and immunosuppressive microenvironments (TME) severely impede therapeutic penetration³. A recent study published in Cell addresses a critical unmet need by introducing a delivery system that successfully circumvents genetic manipulation, actively targets tumors, penetrates tissue effectively, and swiftly triggers a potent immune response (Fig. 1)⁴.

Mast cells (MCs) are widely distributed sentinel cells enriched at mucosal and perivascular interfaces⁵. There is a unique structure of secretory granules located in their cytoplasm. Typically, antigen-mediated crosslinking of IgE bound to FcεRI leads to allergic responses, which initiate degranulation and release of histamine, proteases, and multiple inflammatory cytokines⁶. In oncology, MCs have been regarded as pro-tumorigenic as they are closely associated with angiogenesis and tissue remodeling⁵.

However, leveraging their sophisticated migration and degranulation mechanisms, Xu et al. reversed their role and managed to utilize them for therapeutic purposes. By sensitizing MCs with tumor-specific IgE, such as anti-OVA or anti-HER2, they converted tumor antigens into “allergens” and prepared MCs with tumor-targeting function⁷. Oncolytic adenoviruses (OVs) can be internalized by IgE-sensitized mast cells (IgE-MCs) and intracellularly retained, generating OV-loaded IgE-MCs (OV@IgE-MCs). OVs can selectively infect, replicate within, and damage cancerous cells whilst sparing normal ones⁸. As a result, the OV@IgE-MCs are loaded with OVs and various inflammatory cytokines, ready to deliver OVs and amplify antitumor immunity at the tumor site.

A significant strength of this design lies in its activation mechanisms. Upon systemic administration, IgE-MCs remain quiescent in circulation, shielding OVs from neutralizing antibodies and off-target clearance. Once surface-bound IgEs encounter antigen-dense tumor cells, FcεRI signaling is triggered exquisitely, following rapid degranulation and release of both pre-loaded OVs and endogenous inflammatory mediators. In addition to the direct oncolysis, the pro-inflammatory chemokine storm, particularly CCL3, boosts the immunostimulatory cascade of allergic effects. They increase M1-like macrophage polarization, promote dendritic cell maturation, and recruit CD8⁺ cytotoxic T cells to kill the tumor synergistically. With potent infiltration of IFN-γ⁺ and granzyme B⁺ effector T cells, the IgE-MC therapy enables the suppressive TME to convert into an immunostimulatory status. The therapeutic impact is substantiated across multiple models, including melanoma, breast cancer, lung colonization, as well as patient-derived xenograft (PDX) HER2⁺ models. Notably, human IgE-MCs retain targeting efficacy in the humanized PDX setting, underscoring the promising translational relevance. Safety profiles further indicate minimal risk of systemic anaphylaxis, viral off-target effects, or long-term undesired cell persistence.

The authors emphasized that the IgE-MC platform is not limited to the delivery of OVs but is compatible with diverse therapeutic modalities. Small-molecule drugs, antibodies, nucleic acids, and nanoparticle-based cargos are all possible candidates. With an adapted patient-specific IgE, the versatile system may aid in personalized therapy. Moreover, the study exemplifies that repurposing endogenous cellular programs is of great help for therapeutic gain. Rather than overriding cell identity through genetic engineering, native signaling logic may inspire safer, easier, stronger next-generation cell-based delivery approaches.

Despite the excellence of the IgE-MC delivery platform, several concerns and challenges remain for clinical translation. Current MC sourcing requires either traumatic bone marrow harvesting or prolonged in vitro differentiation from peripheral blood progenitors. These generation processes are labor-intensive and variable, indicating that they are not yet clinically ready⁹. Also, the heterogeneity in FcεRI expression may complicate the standardization and quality control in large-scale manufacturing. Therefore, developing reliable MC production pipelines is essential. Notwithstanding the satisfying results displayed in the experiments, the balance between therapeutic immune activation and unintended allergic responses must be carefully evaluated in various clinical settings.

Xu et al. deliver a compelling and rigorous strategy that redefines MC as a useful tool for immunotherapy. By turning a typical allergic response into an antigen-gated delivery and immune-amplifying system, the study represents a significant conceptual advance in drug delivery, inspiring more fundamentally innovative cell therapy designs. This raises a timely question for the field: how can we harness the intrinsic mechanisms and signaling logic of human cells to simplify engineering, optimize the safety profile, while achieving durable therapeutic benefits.

[1]	Baker, D.J., Arany, Z., Baur, J.A., Epstein, J.A. & June, C.H. Nature 619, 707–715 (2023).

[2]	Bot, A. et al. Nat. Rev. Drug Discov. 25, 116–137 (2026).

[3]	Lutz, H., Hu, S., Dinh, P.-U. & Cheng, K. Med. Drug Discov. 3, 100014 (2019).

[4]	Xu, Y. et al. Cell 189, 872–886 (2026).

[5]	Li, Y. et al. Cell 186, 5719–5738.e28 (2023).

[6]	Chen, M., Su, Q. & Shi, Y. Nature 637, 453–460 (2025).

[7]	McDonnell, J.M., Dhaliwal, B., Sutton, B.J. & Gould, H.J. Annu. Rev. Immunol. 41, 255–275 (2023).

[8]	Chen, Y. et al. Nat. Biotechnol. 42, 1876–1887 (2024).

[9]	St. John, A.L., Rathore, A.P.S., Ginhoux, F. Nat. Rev. Immunol. 23, 55–68 (2023).

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Mao, L., Cheng, K. Mast cells: masters of targeted drug delivery Vita https://doi.org/10.15302/vita.2026.01.0007 ()

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