Inhibiting Endothelial Cell‐Mediated T Lymphocyte Apoptosis with Integrin‐Targeting Peptide‐Drug Conjugate Filaments for Chemoimmunotherapy of Triple‐Negative Breast Cancer

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.