Dual-Targeting Nanoliposome Improves Pro-inflammatory Immunomodulation of the Tumor Microenvironment.

Immunotherapies targeting immune checkpoints have revolutionized cancer treatment by normalizing the immunosuppressive microenvironment of tumors and reducing adverse effects on the immune system. Indoleamine 2,3-dioxygenase (IDO) inhibitors have garnered attention as a promising therapeutic agent for cancer. However, their application alone has shown limited clinical benefits. Cabozantinib, a multitarget tyrosine kinase inhibitor, holds immunomodulatory potential by promoting infiltration and activation of effector cells and inhibiting suppressive immune cells. Despite its potential, cabozantinib as a monotherapy has shown limited efficacy in terms of objective response rate. In this study, IDO-IN-7 and cabozantinib were co-encapsulated into liposomes to enhance tumor accumulation and minimize adverse effects. The liposomal combination exhibited potent cytotoxicity and inhibited the function of IDO enzyme. Furthermore, the dual-targeted treatment effectively inhibited tumor development and reversed the suppressive tumor microenvironment by regulating both adaptive and innate branch of immune system. This was evidenced by pronounced infiltration of T cells and B cells, a decrease of regulatory T lymphocytes, a shift to a pro-inflammatory phenotype of tumor-associated macrophages, and increased levels of neutrophils. This is the first developed of a liposome-delivered combination of IDO inhibitors and cabozantinib, and holds great potential for future clinical application as a promising anti-cancer strategy. This article is protected by copyright. All rights reserved.