AI-Designed Cyclic Peptides Enable Controllable Modulation of the CD28 Immune Checkpoint.
AI-designed cyclic peptides are stepping up in immune checkpoint research. A new study just dropped the details: researchers built a cyclic peptide called CIP-3 that targets the CD28 checkpoint, a key player in T-cell activation. This isn’t just another antibody or biologic. CIP-3 is a synthetic peptide, engineered with AI to lock onto CD28 with nanomolar precision—and, more importantly, you can turn its effects on and off by adjusting exposure.
Adv Sci (Weinh)
by Kuncewicz K, Upadhyay S, Zhu R et al.
“AI-Designed Cyclic Peptides Enable Controllable Modulation of the CD28 Immune Checkpoint. Kuncewicz K(1)(2), Upadhyay S(1), Zhu R(3), Duan H(3), Gabr MT(1). Author information: (1)Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York, USA. (2)Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, Gdansk, Poland. (3)Faculty of Applied Sciences, Macao Polytechnic University, Macao, China. Immune checkpoint therapies have transformed immunotherapy but remain dominated by biologic agents characterized by prolonged receptor occupancy and limited pharmacologic controllability. Although multiple classes of immunomodulatory therapeutics exist, synthetic modalities capable of directly targeting extracellular immune checkpoint protein-protein interaction interfaces while enabling controllable immune modulation remain comparatively underexplored. Here, we report an AI-guided strategy for discovering cyclic peptide antagonists of the costimulatory receptor CD28. The lead peptide, CIP-3, binds the CD28 extracellular domain with nanomolar affinity and disrupts CD28-ligand interactions. In primary human immune systems, CIP-3 suppresses CD28-dependent T-cell activation without intrinsic agonist activity and exhibits rapid pharmacologic reversibility, enabling exposure-dependent control of immune signaling. In a T-cell transfer model of chronic colitis, CIP-3 confers dose-dependent therapeutic efficacy and reduces systemic inflammatory cytokines. CIP-3 also suppresses cytokine production across independent healthy donors and patient-derived PBMCs from individuals with ulcerative colitis with efficacy comparable to a benchmark anti-CD28 biologic. Together, these findings demonstrate the potential of AI-designed cyclic peptides as a controllable synthetic modality for immune checkpoint modulation. © 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH.”
Here’s what stands out:
CIP-3 binds to the CD28 extracellular domain and blocks its usual signaling partners.
No agonist activity, so you’re not accidentally flipping the immune system into overdrive.
Rapid reversibility. Researchers can dial up or down the immune modulation by adjusting peptide levels.
In human immune cell models and a mouse colitis model, CIP-3 suppressed cytokine storms and T-cell activation, matching the performance of benchmark anti-CD28 biologics.
Why care? Biologic immune checkpoint inhibitors are powerful but stick around in the body for a long time. That makes dose control tricky and side effects harder to manage. Synthetic cyclic peptides like CIP-3 could offer the same immune checkpoint control, but with a much tighter handle—think "on-demand" immunomodulation.
For researchers, this is a call to look beyond antibodies. AI-guided peptide design is opening the door to new classes of immune modulators. The tools to build, test, and tune these molecules are already here, and the results speak for themselves.
Curious about the broader field? Check out the peptide research index for more on synthetic peptides in immunology and beyond.
Bottom line: AI-designed cyclic peptides are rewriting the rules on immune checkpoint control, and the research community is just getting started.
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