A Novel d‐Peptide Identified by Mirror‐Image Phage Display Blocks TIGIT/PVR for Cancer Immunotherapy

Abstract The low response rate and adaptive resistance of PD‐1/PD‐L1 blockade demands the studies on novel therapeutic targets for cancer immunotherapy. We discovered that a novel immune checkpoint TIGIT expressed higher than PD‐1 in many tumors especially anti‐PD‐1 resistant tumors. Here, mirror‐image phage display bio‐panning was performed using the d ‐enantiomer of TIGIT synthesized by hydrazide‐based native chemical ligation. d ‐peptide D TBP‐3 was identified, which could occupy the binding interface and effectively block the interaction of TIGIT with its ligand PVR. D TBP‐3 showed proteolytic resistance, tumor tissue penetrating ability, and significant tumor suppressing effects in a CD8 + T cell dependent manner. More importantly, D TBP‐3 could inhibit tumor growth and metastasis in anti‐PD‐1 resistant tumor model. This is the first d ‐peptide targeting TIGIT, which could serve as a potential candidate for cancer immunotherapy.