Enhancing immunotherapy with tumour-responsive nanomaterials

Stephen W Linderman^#^{1

2}, Louis DeRidder^#^{3

4}, Lucía Sanjurjo^{5

6}, Michael B Foote⁷, María José Alonso^{6

8

9}, Ameya R Kirtane¹⁰, Robert Langer^{11

12}, Giovanni Traverso^{13

14

15

16}

Affiliations

¹ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Division of Hospital Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
⁶ Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain.
⁷ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Department of Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain.
⁹ IMDEA Nanosciences Institute, Madrid, Spain.
¹⁰ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. rlanger@mit.edu.
¹² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. rlanger@mit.edu.
¹³ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
¹⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
¹⁵ Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. cgt20@mit.edu.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA. cgt20@mit.edu.

^# Contributed equally.

PMID: 40050505
DOI: 10.1038/s41571-025-01000-6

Review

Enhancing immunotherapy with tumour-responsive nanomaterials

Stephen W Linderman et al. Nat Rev Clin Oncol. 2025 Apr.

. 2025 Apr;22(4):262-282.

doi: 10.1038/s41571-025-01000-6. Epub 2025 Mar 6.

Authors

Affiliations

¹ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Division of Hospital Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
⁶ Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain.
⁷ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Department of Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain.
⁹ IMDEA Nanosciences Institute, Madrid, Spain.
¹⁰ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. rlanger@mit.edu.
¹² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. rlanger@mit.edu.
¹³ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
¹⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
¹⁵ Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. cgt20@mit.edu.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA. cgt20@mit.edu.

^# Contributed equally.

PMID: 40050505
DOI: 10.1038/s41571-025-01000-6

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.

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Conflict of interest statement

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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Enhancing immunotherapy with tumour-responsive nanomaterials

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Enhancing immunotherapy with tumour-responsive nanomaterials

Authors

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Abstract

Conflict of interest statement

References

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