Multi-synergistic chemotherapeutic drug assemblies to activate colorectal cancer immunotherapy by modulating the multilevel immunosuppressive characteristics

Abstract

The life-threatening colorectal cancer exhibits multilevel immunosuppressive characteristics, including low immunogenicity, abnormal cellular metabolism, and acidic immunosuppressive microenvironment. In this work, multi-synergistic chemotherapeutic drug assemblies are fabricated to activate colorectal cancer immunotherapy by modulating the multilevel immunosuppressive characteristics. Without any drug excipients, the glycolysis inhibitor of lonidamine (LON), indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor of NLG919 (NLG), and the photosensitizer of chlorine e6 could self-assemble into drug assemblies (LNC) with uniform nano-size distribution and increased drug stability. Moreover, LNC could also promote cellular uptake and enhance drug penetration to enable efficient drug co-delivery. Especially, the photodynamic therapy (PDT) of LNC could disrupt tumor cells to release tumor-associated antigens, thus efficiently suppressing primary tumor growth and improving tumor immunogenicity. Meanwhile, LNC could also reduce the activity of IDO-1 and attenuate the glycolysis metabolism, thereby reversing the multilevel immunosuppressive characteristics to promote T cell activation. Benefiting from the multi-synergistic effects, LNC efficiently eradicates the primary tumor growth and also activates systemic antitumor immunity for metastatic tumor inhibition. Such a simple formulation but a multi-synergistic strategy may accelerate the development of translational nanomedicine for colorectal cancer immunotherapy by using small molecular drug combinations.