Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors [dataset 3]

Monocyte–derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin accessibility analysis of BM myeloid progenitors, monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. We show that tumors prime accessibility for Nfe2l2 (NRF2) in myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increases during monocyte differentiation in the TME to regulate mo-mac stress response, in turn promoting mo-mac survival and suppressive function. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs’ survival and suppressive programs in the TME, enabling NK and T cell therapeutic antitumor immunity. Altogether, our study identifies a druggable epigenetic node of myeloid progenitor dysregulation that sustains immunosuppressive mo-macs in the TME.