Synergistic Anti-Tumor Efficacy Achieved by Reversing Drug Resistance through the Regulation of the Tumor Immune Microenvironment with IL-12 and Osimertinib Combination Therapy.

ABSTRACT

The objective of this study was to investigate the role of IL-12 in enhancing the anti-tumor efficacy of the small molecule targeted drug osimertinib in resistant tumor models and reversing resistance mechanisms. We utilized paired non-small cell lung cancer H1975 tumor tissues, establishing mouse tumor models with diverse tumor immune microenvironments. Analytical methods including immunohistochemistry and immunofluorescence were employed to compare immune cell infiltration, cytokines, effector molecules, and protein changes in resistant signaling pathways in tumor tissues, shedding light on IL-12's mechanism of action in enhancing osimertinib efficacy and reversing resistance. Results showed that osimertinib monotherapy had limited tumor suppression, whereas IL-12 exhibited more significant anti-tumor effects. Combination therapy groups demonstrated even greater tumor suppression with increased immune cell infiltration, elevated immune-related factor secretion, reduced immunosuppressive MDSCs, and decreased resistance-related signaling pathway markers. In conclusion, IL-12 enhances anti-tumor efficacy and reverses osimertinib resistance through various mechanisms, including increased immune cell infiltration, reduced immunosuppressive MDSCs, enhanced immune cell granzyme and IFN-γ release, decreased PDL-1 expression, improved tumor microenvironment, restored immune surveillance, and heightened cancer cell sensitivity to osimertinib.