• Publication: 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 

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.

Kea 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.