Overview

• Mount Sinai researchers report in Nature that lung cancer cues deliver an early "first hit" in bone marrow myeloid progenitors that predisposes them to become tumor-supporting macrophages.
• Single-cell transcriptomic and epigenomic mapping across mouse models and human NSCLC traced progenitors into tumor-infiltrating monocyte-derived macrophages.
• Data support a two-hit model marked by diminished interferon signaling and increased oxidative stress programs in GMPs and cMoPs that persist in TREM2hi/Arg1hi macrophages inside tumors.
• NRF2 inhibition with Brusatol or ML385 reduced immunosuppressive macrophage formation and improved tumor control in mice, with stronger effects when combined with anti-PD-1 therapy.
• The work, published September 10 in Nature, provides a preclinical rationale for NRF2–immunotherapy combinations and proposes blood tests to detect tumor-educated progenitors, with clinical validation still pending.