Hegde, S.; Giotti, B.; Soong, B. Y.; Halasz, L.; Le Berichel, J.; Magen, A.; Kloeckner, B.; Mattiuz, R.; Park, M. D.; Marks, A.; Belabed, M.; Hamon, P.; Chin, T.; Troncoso, L.; Lee, J. J.; Ahimovic, D.; Bale, M.; Chung, G.; D'souza, D.; Angeliadis, K.; Dawson, T.; Kim-Schulze, S.; Flores, R. M.; Kaufman, A. J.; Ginhoux, F.; Josefowicz, S. Z.; Ma, S.; Tsankov, A. M.; Marron, T. U.; Brown, B. D.; Merad, M.

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 analysis over the continuum of BM myeloid progenitors, circulating 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. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-mac survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.