Inhibiting Endothelial Cell‐Mediated T Lymphocyte Apoptosis with Integrin‐Targeting Peptide‐Drug Conjugate Filaments for Chemoimmunotherapy of Triple‐Negative Breast Cancer
Ying Cai, Binyu Zhu, Xiaoting Shan, Lingli Zhou, Xujie Sun, Anqi Xia, Binhao Wu, Yang Yu, Helen He Zhu, Pengcheng Zhang, Yaping Li
Abstract
Abstract Tumor‐associated endothelial cells (TECs) limit antitumor immunity via inducing apoptosis of infiltrating T lymphocytes through a Fas ligand (FasL) mediated mechanism. Herein, this work creates a peptide‐drug conjugate (PDC) by linking 7‐ethyl‐10‐hydroxycamptothecin (SN38) to hydrophilic segments with either RGDR or HKD motif at their C‐terminus through a glutathione‐responsive linker. The PDCs spontaneously assemble into filaments in aqueous solution. The PDC filaments containing 1% of SN38‐RGDR (SN38‐HKD/RGDR) effectively target triple‐negative breast cancer (TNBC) cells and TECs with upregulated expression of integrin, and induce immunogenic cell death (ICD) of tumor cells and FasL downregulation of TECs. SN38‐HKD/RGDR increases infiltration, activity, and viability of CD8 + T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin‐targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy.