Autophagic adaptation to oxidative stress alters peritoneal residential macrophage survival and ovarian cancer metastasis

Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression. Tim-(4+) TAMs were embryonically originated and locally sustained while Tim-4(-) TAMs were replenished from circulating monocytes. Tim-4(+) TAMs, but not Tim-4(-) TAMs, promoted tumor growth in vivo. Relative to Tim-4(-) TAMs, Tim-4(+) TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4(+) TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family-interacting protein of 200 kDa resulted in Tim-4(+) TAM loss via ROS-mediated apoptosis and elevated T cell immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer-associated macrophages positive for complement receptor of the immunoglobulin superfamily (CRIg) were transcriptionally, metabolically, and functionally similar to murine Tim-4(+) TAMs. Thus, targeting CRIg(+) (Tim-4(+)) TAMs may potentially treat patients with ovarian cancer with peritoneal metastasis.