Macrophages rescue cells from ferroptotic death

Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation, has a key role in organ injury, degenerative disease, and vulnerability of therapy-resistant cancers. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we demonstrate that macrophages co-cultured with ferroptotic cancer cells from various types effectively mitigate cell death induced by GPX4 inhibitors (RSL3 and ML162), GPX4 silencing via shRNA, or the Xc- system inhibitor IKE. Furthermore, macrophages effectively reduced lipid peroxidation in ferroptotic cells. Importantly, macrophage function relies on direct cell-to-cell contact and is affected by their differentiation. Specifically, polarization into M1 macrophages, but not M2, greatly hinders their protective capabilities. Interestingly, unlike apoptotic cells, ferroptotic cells retain elevated levels of the ‘don’t eat me’ signal, CD47, and conversely, fail to present the “eat me” signal phosphatidylserine (PS) on the outer layer of the plasma membrane, providing an opportunity for their rescue. Furthermore, in placental villi explants, macrophages protect trophoblasts from ferroptotic death. These results underscore the intricate interplay between ferroptotic cells and their microenvironment and provide compelling evidence of a yet-unrecognized anti-ferroptotic activity of macrophages as a cell-extrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.