A Supramolecular "Trident" for Cancer Immunotherapy

Immunotherapy has shown great promise for the treatment of cancer. However, the limited efficacy of single-agent immunotherapy hinders its widespread application, which stimulated the investigation of combination therapy with improved efficacy. Herein, a tri-functional immunostimulatory supramolecular nanomedicine consisting of indoximod (IND, an indoleamine 2,3-dioxygenase (IDO) inhibitor), (D)PPA-1 (a D-peptide antagonist against programmed cell death ligand-1 (PD-L1)), and a self-assembling D-tetrapeptide of G(D)F(D)F(D)Y (a powerful adjuvant with immunostimulatory properties) is reported. The resulting IND-G(D)F(D)F(D)Y-(D)PPA-1 behaves as a supramolecular "trident," and its three functional parts play parallel roles to boost the effective immune responses. It is shown that the supramolecular "trident" exhibits a stronger binding ability to PD-L1 than the (D)PPA-1 peptide (>fourfold) and is able to inhibit the IDO-1 pathway more efficiently than IND itself. The supramolecular "trident" activates and recruits the cytotoxic CD8(+) T lymphocytes along with other immune effector cells in tumors, concomitant with downregulation of Foxp3(+) T cells and upregulation of tumor immune-related cytokines, thus showing a strong ability to improve the tumor microenvironment and enhance immunotherapeutic effects to prevent tumor growth and metastasis in the breast tumor model. The findings may stimulate the development of self-assembling peptide-based multifunctional nanomedicines for cancer therapy.