A Novel D Peptide Identified by Mirror-image Phage Display Blocks TIGIT/PVR for Cancer Immunotherapy.

: 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.