Synergistic mechanisms and clinical translation of regorafenib combination therapies.

The evolution of regorafenib from a monotherapy to a cornerstone of combination regimens for advanced solid tumors is fueled by its unique multi-targeted profile. This review systematically delineates the synergistic mechanisms underpinning this evolution, encompassing the potent induction of diverse cell death programs (apoptosis, autophagy, ferroptosis), the vertical and horizontal blockade of oncogenic signaling pathways (MAPK, PI3K/AKT, STAT3), and the critical remodeling of the TME. These mechanistic rationales are critically translated into clinical practice, with combinations, particularly with immune checkpoint inhibitors, demonstrating breakthrough efficacy in challenging settings such as microsatellite-stable colorectal cancer and hepatocellular carcinoma. We further synthesize strategies to overcome resistance-from targeting compensatory pathways to employing novel nanocarriers for optimized drug delivery-and outline the future landscape, emphasizing the imperative for biomarker-driven patient selection and the integration of next-generation agents.