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  • Review Article
  • Published:

Enhancing immunotherapy with tumour-responsive nanomaterials

Nature Reviews Clinical Oncology volume 22, pages 262–282 (2025)Cite this article

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Abstract

The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies. Highlighting preclinical successes and ongoing clinical trials, we evaluate the current landscape and potential of these innovative approaches. We also consider future research directions as well as the most important barriers to successful clinical translation, emphasizing the transformative potential of tumour-responsive nanomaterials in overcoming the barriers that limit the activity of traditional immunotherapies, thus improving patient outcomes.

Key points

  • Tumours can develop complex immunosuppressive microenvironmental and metabolic features, enabling immune escape, evasion and growth.

  • Tumour-responsive nanomaterials can target these features for immunotherapy delivery, including tumour-specific activation and cargo release to restore a functional cancer–immunity cycle.

  • Despite abundant preclinical evidence of antitumour activity, clinical translation of immune-nanomedicines has thus far been slow and several major barriers continue to impede progress.

  • Promising future directions include improved immunotherapy cargoes, improved tumour specificity by leveraging multiple tumour-responsive properties, and optimized delivery strategies enabling improved pharmacodynamics.

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Fig. 1: Key properties of an immunosuppressive TME in the context of the cancer–immunity cycle.
Fig. 2: Mechanisms of cargo release from tumour-responsive nanomaterials.
Fig. 3: Functional motifs that give rise to tumour-specific responsiveness.
Fig. 4: Incorporating drug cargoes to turn nanomaterials into immunotherapies.

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  1. These authors contributed equally: Stephen W. Linderman, Louis DeRidder.

Authors and Affiliations

  1. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Stephen W. Linderman, Robert Langer & Giovanni Traverso

  2. Division of Hospital Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Stephen W. Linderman

  3. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Louis DeRidder, Robert Langer & Giovanni Traverso

  4. Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Louis DeRidder

  5. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

    Lucía Sanjurjo

  6. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain

    Lucía Sanjurjo & María José Alonso

  7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Michael B. Foote

  8. Department of Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain

    María José Alonso

  9. IMDEA Nanosciences Institute, Madrid, Spain

    María José Alonso

  10. Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA

    Ameya R. Kirtane

  11. Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Giovanni Traverso

  12. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Giovanni Traverso

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Contributions

S.W.L., L.D., M.B.F., A.R.K. and G.T. researched data for the manuscript and made a substantial contribution to discussions of content, S.W.L., L.D., L.S., M.B.F., M.J.A., A.R.K. and G.T. wrote the manuscript. All authors edited and/or reviewed the manuscript prior to submission.

Corresponding authors

Correspondence to Robert Langer or Giovanni Traverso.

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Competing interests

S.W.L. is a consultant of the Vaccine and Immunotherapy Center at Massachusetts General Hospital, is on the advisory board of Contrast AI, Inc., is CEO and on the Board of Directors of Absco Therapeutics, Inc., a biotechnology company focused on the development of novel materials-based approaches for immunotherapy, and is on the Board of Directors of Sling Health, a nonprofit biotechnology incubator. M.B.F. has received honoraria for acting as an advisor for Abbott, Bristol Meyers Squibb and Genzyme. M.J.A. has financial interests in Libera Bio, Inc., a company related to immunotherapy. A complete list of R.L.’s competing interests is provided in Supplementary table 2. G.T. is on the board of directors of Absco Therapeutics, Inc. Complete details of all relationships (for profit and not for profit) are provided in Supplementary table 3. The authors are listed as co-inventors on multiple patent applications in the area of cancer therapy, including technologies applicable to immunological-based therapeutic interventions for cancer and in personalization of drug dosing through closed-loop drug delivery, these include US Patent application numbers:: 18/417,024 and 63/527,168.

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Nature Reviews Clinical Oncology thanks X. Chen, H. Gao, Z, Luo, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Linderman, S.W., DeRidder, L., Sanjurjo, L. et al. Enhancing immunotherapy with tumour-responsive nanomaterials. Nat Rev Clin Oncol 22, 262–282 (2025). https://doi.org/10.1038/s41571-025-01000-6

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