A Totipotent “All‐In‐One” Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment

Abstract

Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti‐tumor immunity, which can be achieved by using multiple‐agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct “all‐in‐one” totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high‐content peptide library is designed. By using the “3D‐molecular‐evolution” screening strategy, an efficient and totipotent “all‐in‐one” peptide (TAP) is obtained, which possesses the abilities of self‐assembling, blocking the PD‐1/PD‐L1 axis, inhibiting Rbm38‐eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient‐derived xenografts, PD‐L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody‐based drugs.

Dual-Functional Capping Agent-Mediated Transformation of Silver Nanotriangles to Silver Nanoclusters for Dual-Mode Biosensing

“…On the other hand, dual-signal detection provides complementary information to avoid false positive signals and environmental interference. 42,43 As shown in Figure 4A,B,D, after treatment with various concentrations of trypsin, the color and absorption/fluorescence spectra of the BSA-mediated AgNT biosensors were consistent with the above-mentioned thiolated-mediated change in AgNTs. However, the response in color change, the LSPR peak shift, and fluorescence intensity in the samples with pepsin treatment were completely opposite to the experiments within trypsin (Figure S4).…”

“…On the one hand, the robust response signal from the BSA-mediated sensing strategy could be read by the naked eye under ambient conditions. On the other hand, dual-signal detection provides complementary information to avoid false positive signals and environmental interference. , …”

Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy

“…Researchers created TPA, a combined targeted peptide that inhibited the PD-1/PD-L1 axis, activated p53, and showed tumor killing and immunotherapeutic sensitization effects on a humanized PBMCengrafted PDX model. There is now a potential pathway for the development of self-assembled peptide drugs for cancer therapy (105). For tumor targeting, the researchers synthesized size-tunable nanostructures with a spherical morphology by combining partially reductive HSA with hydrophobic Fluvastatin, known as According to the study, these nanodrugs effectively enhanced the potency of Anti-PD1 antibodies against colon cancer in a humanized CRC-PDX mouse model while maintaining acceptable levels of safety (100).…”

Construction of Targeting-Peptide-Based Imaging Reagents and Their Application in Bioimaging

“…Upon entry into tumor cells, it blocks the formation of the Rbm38-eIF4E complex, thereby upregulating p53. Reprinted with permission from ref . Copyright 2023 Wiley.…”

“…In the TME, TAP can transform into α-helical structures and assemble into dense nanofibers under the recruitment of PD-L1, thus blocking the PD-1/PD-L1 axis. After entering the tumor cells, it blocks the formation of the Rbm38-eIF4E complex, thus upregulating p53 (Figure c) . It should be noted that the α-helical entropy value is low and the hydrogen-bonding network is blocked inside the peptide, leading to its poor stability.…”