Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (T-eff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/T-eff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface alpha(3)beta(1) integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures T-eff cells via the activatable alpha(4)beta(1) integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.

Automated summary

This study reports a programmable tumor cells/T-eff cells bispecific nano-immunoengager that can enhance the efficacy of immune checkpoint blockade therapy by improving T cell infiltration and modulating the immunosuppressive tumor microenvironment.