M2-LIKE TAM VIA STAT3/NF-ΚB SIGNALING AXIS AS TARGET OF IMMUNOMODULATORY THERAPY WITH HA-COATED PEIPLGA-MTX NANOPARTICLES AND ANTI-PD-L1 CHECKPOINT BLOCKER IN THE BREAST CANCER
Immunomodulation, PLGA nanoparticles, STAT3, NF-kB, tumor microenvironment
Inflammation associated with the tumor microenvironment plays a critical role in the growth and progression of cancer, and immunotherapeutic strategies that aim to modulate the immune response in cancer have been crucial. In this study, a PLGA-based drug nanocarrier covered with polyethyleneimine (Pei) and hyaluronic acid (HA) was developed and associated with an anti-PD-L1 immune checkpoint inhibitor to investigate the anti-cancer and immunomodulatory performance in the breast cancer. From the allographic tumor induction model, the combined therapy altered tumorigenic course as well as promoting immunomodulation in tumor microenvironment with a significant reduction in primary tumor and metastasis. For the first time, our findings suggest the presence of an IL-10-STAT3-NF-κB signaling axis mediated by M2 macrophage in breast cancer. Importantly, the triggered NF-κB/STAT3-mediated signaling suppression by our treatment seems to have disrupted the communication between immune and cancer cells, reducing critical pro-tumor events such as: immune escape; cell survival; drug and apoptosis resistance, as well as some key mechanisms in EMT. These results contribute to our understanding of the immunological mechanisms that underlie the anti-tumorigenic effects of an effective and promising drug nanocarrier capable of satisfactorily immunomodulating the tumor microenvironment and providing a favorable outcome in breast cancer.