Glucocorticoid Receptor-Targeted Nanoliposome for STAT3 Inhibition-Led Myeloid-Derived Suppressor Cell Modulation and Efficient Colon Cancer Treatment.

Abstract

STAT3 is an important protein responsible for cellular proliferation, motility, and immune tolerance and is hyperactive in colorectal cancer, instigating metastasis, cellular proliferation, migration, as well as inhibition. It helps in proliferation of myeloid-derived suppressor cells (MDSCs), which within the tumor microenvironment (TME) suppress T cells to encourage tumor growth, metastasis, and resistance to immunotherapy, besides playing dynamic role in regulating macrophages within the tumor. Thus, MDSC is a potential target to augment immune surveillance within the TME. Herein, we report targeting both colorectal cancer and MDSCs using a glucocorticoid receptor (GR)-targeted nanoliposomal formulation carrying GR-ligand, dexamethasone (Dex), and a STAT3 inhibitor, niclosamide (N). Our main objective was to selectively inhibit STAT3, the key immunomodulatory factor in most TME-associated cells including MDSCs, and also repurpose the use of this antihelminthic, low-cost drug N for cancer treatment. The resultant formulation D1XN exhibited better tumor regression and survivability compared to GR nontargeted formulation. Further, bone marrow cell-derived MDSCs were engineered by D1XN treatment ex vivo and were inoculated back to tumor-bearing mice. Significant tumor growth inhibition with enhanced antiproliferative immune cell signatures, such as T cell infiltration, decrease in T_reg cells, and increased M1/M2 macrophage ratio within the TME were observed. This reveals the effectiveness of engineered MDSCs to modulate tumor surveillance besides reversing the aggressiveness of the tumor. Therefore, D1XN and D1XN-mediated engineered MDSCs alone or in combination can be considered as potent selective chemo-immunotherapeutic nanoliposomal agent(s) against colorectal cancer.