Dual-Targeting Nanoliposome Improves Proinflammatory 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 are coencapsulated into liposomes to enhance tumor accumulation and minimize adverse effects. The liposomal combination exhibits potent cytotoxicity and inhibits the function of IDO enzyme. Furthermore, the dual-targeted treatment effectively inhibits tumor development and reverses the suppressive tumor microenvironment by regulating both adaptive and innate branch of immune system. This is evidenced by pronounced infiltration of T cells and B cells, a decrease of regulatory T lymphocytes, a shift to a proinflammatory phenotype of tumor-associated macrophages, and increases 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 anticancer strategy. A clinical standard liposome system is employed to simultaneously deliver cabozantinib and indoleamine 2,3-dioxygenase inhibitor, and thereby exhibit improved anti-tumor efficacy, which shows high biocompability and safety. After PEGlyation on the surface of the liposomes, high tumor accumalation can be achieved due to the prolonged ciculation, leading to boosted immune response and regulated tumor microenvironment.image