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Sensitization of tumours to immunotherapy by boosting early type-I interferon responses enables epitope spreading

Sadeem Qdaisat1,2, Brandon Wummer1, Brian D Stover3

  • 1Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.

Nature Biomedical Engineering
|July 18, 2025
PubMed

Insights

Early type-I interferon responses are key for cancer immunotherapy success, even in difficult tumors. Boosting these responses with RNA-loaded particles enhances immunity and promotes tumor rejection, offering new treatment strategies.

Area of Science:

  • Immunology
  • Oncology
  • Virology

Background:

  • Cancer immunotherapies, including immune checkpoint inhibitors, often depend on targeting neoepitopes, favoring tumors with high mutational burden.
  • Poorly immunogenic tumors frequently exhibit resistance to current immunotherapies due to a lack of effective immune responses.

Purpose of the Study:

  • To investigate the role of early type-I interferon responses in mediating the success of immune checkpoint inhibitors.
  • To explore methods for enhancing interferon responses to overcome immunotherapy resistance in poorly immunogenic tumors.
  • To determine if boosting interferon responses can induce epitope spreading and improve anti-tumor immunity.

Main Methods:

  • Utilized mouse models of cancer immunotherapy.
  • Administered lipid particles loaded with RNA encoding tumor-unspecific antigens to enhance type-I interferon responses.
  • Transferred immune responses from sensitive to resistant tumors.
  • Assessed tumor immunity, epitope spreading, and protection against tumor rechallenge.

Main Results:

  • Early type-I interferon responses were found to mediate the success of immune checkpoint inhibitors and promote epitope spreading in poorly immunogenic tumors.
  • Systemic administration of RNA-loaded lipid particles effectively enhanced these crucial interferon responses.
  • Immune responses from immunotherapy-sensitive tumors were transferable to resistant tumors, leading to heightened immunity and protection.
  • Restoring a damage response through boosted interferon signaling enabled epitope spreading and self-amplifying immunity in treatment-refractory tumors.

Conclusions:

  • The efficacy of cancer immunotherapy is significantly influenced by early type-I interferon signaling.
  • Boosting type-I interferon responses can overcome immunotherapy resistance in tumors by inducing epitope spreading and enhancing anti-tumor immunity.
  • This approach holds promise for treating a broader range of cancers, including those currently refractory to immunotherapy.

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