Hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. Here, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of IL-1α that drives the enhanced myeloid response. The age-associated decline of DNMT3A enhances IL-1α production, and disrupting IL-1R1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1α-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies. (125 words)