Redirecting immune signaling with cytokine adaptors

Gita C. Abhiraman, Karsten D. Householder, Grayson E. Rodriguez, Caleb R. Glassman, Robert A. Saxton, Cort B. Breuer, Steven C. Wilson, Leon Su, Michelle Yen, Cynthia Hsu, Venu G. Pillarisetty, Nathan E. Reticker-Flynn and K. Christopher Garcia ()
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Gita C. Abhiraman: Stanford University School of Medicine
Karsten D. Householder: Stanford University School of Medicine
Grayson E. Rodriguez: Stanford University School of Medicine
Caleb R. Glassman: Stanford University School of Medicine
Robert A. Saxton: Stanford University School of Medicine
Cort B. Breuer: Stanford University School of Medicine
Steven C. Wilson: Stanford University School of Medicine
Leon Su: Stanford University School of Medicine
Michelle Yen: Stanford University School of Medicine
Cynthia Hsu: University of Washington School of Medicine
Venu G. Pillarisetty: University of Washington School of Medicine
Nathan E. Reticker-Flynn: Stanford University School of Medicine
K. Christopher Garcia: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Cytokines are signaling molecules that coordinate complex immune processes and are frequently dysregulated in disease. While cytokine blockade has become a common therapeutic modality, cytokine agonism has had limited utility due to the widespread expression of cytokine receptors with pleiotropic effects. To overcome this limitation, we devise an approach to engineer molecular switches, termed cytokine adaptors, that transform one cytokine signal into an alternative signal with a different functional output. Endogenous cytokines act to nucleate the adaptors, converting the cytokine–adaptor complex into a surrogate agonist for a different cytokine pathway. In this way, cytokine adaptors, which have no intrinsic agonist activity, can function as conditional, context-dependent agonists. We develop cytokine adaptors that convert IL-10 or TGF-β into IL-2 receptor agonists to reverse T cell suppression. We also convert the pro-inflammatory cytokines IL-23 or IL-17 into immunosuppressive IL-10 receptor agonists. Thus, we show that cytokine adaptors can convert immunosuppressive cytokines into immunostimulatory cytokines, or vice versa. Unlike other methods of immune conversion that require cell engineering, cytokine adaptors are soluble molecules that leverage endogenous cues from the microenvironment to drive context-specific signaling.

Date: 2025
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DOI: 10.1038/s41467-025-57681-1

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