Chemotherapy based on “Domino-effect” combined with immunotherapy amplifying the efficacy of an anti-metastatic treatment

Abstract

In tumor immunotherapy, Treg cells are immunosuppressive cells. In general, the main strategy of chemo immune-therapy for Treg cells is to eliminate them using chemotherapy drugs combined with immune checkpoint inhibitors. However, the dead Treg cells still exert immunosuppressive effects via the nucleoside adenosine pathway. To improve immunosuppression, we designed a nanosystem to deliver synthetic chemotherapeutics and immune activators. The homemade curcumin analog (CA) was encapsulated by α-lactalbumin (α-LA), and the Treg cell specific antibody (mAb), as a therapeutic agent, was linked to the drug-loaded protein via matrix metalloproteinase-responded peptide (P). After the cleavage peptide responded to matrix metalloproteinase (MMP-2), the CA@α-LA-P-mAb nanoparticles were separated into CA@α-LA and antibody, which can specifically enter cancer cells and Treg cells via membrane fusion and Nrp-1 receptors, respectively. Finally, we found that CA can not only lead to cell death by the chondriosome apoptosis approach but also reduce the production of Treg cells by inhibiting the expression of foxp3 (a key transcription factor of Treg cells). In addition, specific antibodies can improve the immunosuppression of existing Treg cells. The combined effect of CA and antibodies amplifies the role of chemotherapy in metastatic breast cancer.