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Engineering innate immune cells for cancer immunotherapy

Nature Biotechnology volume 43, pages 516–533 (2025)Cite this article

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Abstract

Innate immune cells, including natural killer cells, macrophages and γδ T cells, are gaining prominence as promising candidates for cancer immunotherapy. Unlike conventional T cells, these cells possess attributes such as inherent antitumor activity, rapid immune responses, favorable safety profiles and the ability to target diverse malignancies without requiring prior antigen sensitization. In this Review, we examine the engineering strategies used to enhance their anticancer potential. We discuss challenges associated with each cell type and summarize insights from preclinical and clinical work. We propose strategies to address existing barriers, providing a perspective on the advancement of innate immune engineering as a powerful modality in anticancer treatment.

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Fig. 1: Schematic overview of engineering strategies for NK cells in cancer immunotherapies.
Fig. 2: Schematic overview of engineering strategies for myeloid cells in cancer immunotherapies.
Fig. 3: Schematic overview of generation strategies for CAR macrophages in cancer therapy.
Fig. 4: Schematic overview of engineering strategies for γδ T cells in cancer immunotherapies.
Fig. 5: Common engineering strategies shared among the three major innate immune cell types and between any two cell types based on intrinsic immune function.

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Author information

Author notes

  1. These authors contributed equally: Mubin Tarannum, Xizhong Ding, Marta Barisa.

  2. These authors jointly supervised this work: Rizwan Romee, Jin Zhang, John Anderson.

Authors and Affiliations

  1. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    Mubin Tarannum & Rizwan Romee

  2. Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China

    Xizhong Ding & Jin Zhang

  3. Cancer Section, Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK

    Marta Barisa & John Anderson

  4. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Sabrina Hu

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Correspondence to John Anderson, Rizwan Romee or Jin Zhang.

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Competing interests

R.R. is cofounder of InnDura Therapeutics, is a Scientific Advisory Board member of Glycostem Therapeutics and receives funding from Parker Institute for Cancer Immunotherapy and Miltenyi Biotech. J.Z. is a scientific founder of CellOrigin Biotech. J.A. holds founder stock in Autolus, Ltd., and is the inventor on patents related to CAR T cell function.

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Tarannum, M., Ding, X., Barisa, M. et al. Engineering innate immune cells for cancer immunotherapy. Nat Biotechnol 43, 516–533 (2025). https://doi.org/10.1038/s41587-025-02629-5

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