一种新型环肽类TIM-3拮抗剂，通过激活衰竭的T细胞功能，应用于癌症免疫治疗领域。

Abstract

A cyclic peptide binding with TIM-3, TBP1, was screened by a novel CX 12 C cyclic peptide display library base on bacterial surface display. • TBP1 effectively disrupted TIM-3 interactions with CEACAM-1 and PtdSer. • TBP1 restored the function of exhausted T cells in vitro . • TBP1 synergized with anti-PD-1 antibody, improving anti-tumor immunity in vivo . Immune checkpoint blockade (ICB) therapies, particularly antibodies blocking, the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), have shown clinical success but remain limited by suboptimal response rates, often due to insufficient immune activation. T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3), a non-redundant immune checkpoint frequently co-expressed with PD-1, drives severe T-cell exhaustion in solid tumors and contributes to resistance against anti-PD-1/PD-L1 therapy. Thus, dual blockade of TIM-3 and PD-1 may restore more effective anti-tumor immunity. Compared to antibodies, low-molecular-weight peptides offer advantages in combination therapy, including better tissue penetration, lower immunogenicity, improved tolerability and low production costs. Cyclic peptides, in particular, provide enhanced biological activity and proteolytic stability. Here, we present TBP1, a cyclic peptide identified via a bacterial surface display library, which binds TIM-3 with high affinity and specificity. Competitive blocking assays and molecular docking confirmed that TBP1 effectively disrupts TIM-3 interactions with Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) and Phosphatidylserine (PtdSer). In vitro , TBP1 restored exhausted T-cell function by disrupting the TIM-3/CEACAM-1 interaction. In CT26 tumor-bearing mice, TBP1 synergized with an anti-PD-1 antibody, enhancing anti-tumor immunity by promoting CD4 + T cell infiltration and IL-2 secretion. These findings identify TBP1 as a novel TIM-3-targeting cyclic peptide and support its potential a