Cancer Cell Mediated Mitochondrial Transfer Reprograms Macrophage Metabolism and Polarization 2309895

Abstract Introduction Mitochondria are regulators of cellular metabolisms, redox balance, and survival. Their dysfunction has been shown to affect cancer progression and immune regulation. Recent studies have shown mitochondria are dynamic and can be transferred between cells. However, mitochondrial transfer between tumor and immune cells is understudied. Macrophages are the most abundant immune cells in the tumor microenvironment and exhibit plasticity. Understanding how tumor cells manipulate macrophage plasticity through mitochondrial transfer could be crucial for understanding tumor immune regulation. Methods Human breast, prostate, and lung cancer cell lines were used to create bulk tumor and CSC populations. The tumor cells mitochondria were fluorescently labeled and co-cultured with human monocytes. Live cell imaging of the co-culture was used to quantify mitochondrial transfer over 48 hours. A phagocytosis inhibitor was used to identify the possible mechanism of transfer. Results Mitochondrial transfer from tumor cells to macrophages was observed in all cancer types tested. Both bulk tumor cells and CSCs showed mitochondrial transfer to macrophages. CSCs showed greater and more persistent mitochondrial donation over time. Inhibition of phagocytosis reduced mitochondrial uptake in macrophages, but did not completely inhibit transfer, indicating additional mechanisms of uptake were used. The dynamics and magnitude of mitochondrial transfer differed among tumor types, suggesting that tumor type influences immune cell organelle exchange. Conclusion This project provides evidence that tumor cells directly transfer their mitochondria to macrophages, showing a novel mechanism of tumor to macrophage communication. These findings establish the foundation to investigate how tumor mitochondria contribute to macrophage metabolic reprogramming and dichotomy. Funding Source NCI (R03CA293129) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)