Succinate-mediated SUCNR1 activation in tumor-associated macrophages promotes M2 polarization and cetuximab resistance in colorectal cancer: in vitro and in vivo insights.

Colorectal cancer (CRC) ranks among the most prevalent and lethal malignancies globally, with Cetuximab (CTx) resistance being a significant hurdle in its treatment. To uncover the underlying mechanisms, this study recruited 27 metastatic CRC patients undergoing CTx-based therapy and categorized them into responder and non-responder groups. In addition to measuring succinate levels in serum and tumor tissues and evaluating M2 macrophage infiltration in patients, a series of in vitro and in vivo experiments were conducted. In vitro, HT29 and Caco2 cells were treated with CTx and succinate under different conditions, including monoculture and co-culture with macrophages. The results indicated that succinate enhanced CRC cells' resistance to CTx specifically in the presence of macrophages by promoting M2 macrophage polarization. This effect was found to be mediated by succinate receptor 1 (SUCNR1), as demonstrated by experiments involving SUCNR1 knockdown. In vivo, the addition of succinate promoted tumor growth and weakened the inhibitory effect of CTx through macrophages. Further exploration revealed that succinate-induced polarized tumor-associated macrophages secreted IL-6, which played a crucial role in conferring CTx resistance. Overall, this study uncovers that tumor-secreted succinate confers CTx resistance in CRC by activating SUCNR1, thereby driving M2 macrophage polarization. These findings offer novel insights into the mechanisms of CRC resistance and identify potential therapeutic targets within the tumor microenvironment, which could potentially lead to the development of more effective treatment strategies for CRC patients.