Bispecific tumor-penetrating protein anti-EGFR-iRGD efficiently enhances the infiltration of lymphocytes in gastric cancer.

Efficient trafficking of lymphocytes to the tumor microenvironment is crucial for the success of an effective antitumor immunotherapy. A major challenge to achieve effective adoptive immunotherapy is poor tumor penetration and inefficient migration of T cells to the tumor site. Several approaches to facilitate the trafficking of lymphocytes to the tumor microenvironment have been suggested to overcome these obstacles. Here, we address this issue with a focus on the tumor-penetrating peptide iRGD, which can specifically increase the permeability of the tumor vasculature and tumor tissue, enhancing drug penetration. We previously constructed a bispecific tumor-penetrating protein, anti-EGFR-iRGD, which consists of the variable region of the heavy chain of anti-EGFR antibody and a tumor-penetrating peptide iRGD, and verified its ability to improve the penetration of antitumor drugs. Herein, we introduce a novel method of co-administering T cells and anti-EGFR-iRGD to enhance the trafficking, penetration and antitumoral activity of T cells. Our results provide new insights for effectively enhancing T-cell infiltration in tumors and demonstrate a preclinical translational approach for the use of anti-EGFR-iRGD as a therapeutic modifier of cancer immunotherapy to improve clinical outcomes.