Lung tumors rewire immune cells in the bone marrow before they reach cancer sites

Lung tumors don’t just evade the immune system. They reshape it at its source. Researchers from the Icahn School of Medicine at Mount Sinai and collaborators report in the September 10 online issue of Nature [10.1038/s41586-025-09493-y] that tumors rewire immune cells in the bone marrow before they even reach the cancer, suggesting a new target to enhance the durability of current immunotherapy.

Immunotherapies, which rally the body’s defenses against cancer, have transformed care for many patients. But in solid tumors like non-small cell lung cancer (NSCLC), their success is often blunted by an influx of pro-tumoral macrophages-immune cells that suppress the body’s anti-cancer response. Until now, scientists thought these macrophages turned rogue only after reaching the tumor.

The study turns that idea on its head. By mapping individual cells using advanced single-cell genomic tools, the scientists traced bone marrow myeloid progenitor cells-precursors of macrophages-and found that cues from the tumor deliver a “first hit” in these cells. This hit biased the bone marrow progenitor toward a pro-cancer function. A “second hit” inside the tumor seals their pro-cancer function.

“This work changes the way we think about the timing of immune suppression in cancer,” says lead author Samarth Hegde, PhD, a postdoctoral fellow in the laboratory of Miriam Merad, MD, PhD, Chair of Immunology and Immunotherapy, and Director of the Marc and Jennifer Lipschultz Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai.

Our findings show that some of these immune cells are already being reprogrammed in the bone marrow, long before they ever reach the tumor. If we wait to target and rewire them until they’re inside the tumor, it may already be too late to reverse that process. We need strategies to intervene much earlier, while these cells are still developing, so we can stop them from becoming cancer’s allies in the first place.”

Samarth Hegde, PhD, lead author

One potential target, report the investigators, is a protein called NRF2, which helps cells cope with stress. The team found that bone marrow progenitor cells educated by tumor inflammation rewire NRF2, a change that is activated fully once the cells became tumor-infiltrating immunosuppressive macrophages in both patients and mice. When the scientists blocked NRF2, either by altering the gene or with experimental drugs, fewer immune-suppressing macrophages formed, and the immune system mounted a stronger attack against the cancer in preclinical studies.

“Our findings provide a strong rationale for pairing NRF2 inhibitors with today’s immunotherapies,” says senior corresponding author Dr. Merad. “Right now, many treatments focus on what’s happening inside the tumor, but by then, these immune-suppressing macrophages are already fully equipped to help the cancer. If we can target these cells before they leave the bone marrow, we may be able to cut off their supply and tip the fight back in the immune system’s favor.”

The research team believes their work could also lead to blood-based tests that detect “pre-programmed” immune cells, allowing for earlier intervention in patients with NSCLC and for monitoring remission.

Next, the team plans to explore whether the same genetic switches that drive the overproduction of certain immune cells in lung cancer might also be at work in other cancers and in inflammatory conditions such as aging, obesity, and atherosclerosis. They also aim to investigate whether the unusual growth of these immune cells outside the bone marrow, as seen in some cancers, is governed by similar genetic controls. Finally, they will take a closer look at how key molecular pathways, such as NRF2 signaling, influence the metabolism of these immune cells to help tumors escape the body’s defenses.

The paper is titled “Myeloid Progenitor dysregulation fuels immunosuppressive macrophages in tumors.”

The study’s authors, as listed in the journal, are Samarth Hegde, Bruno Giotti, Brian Y. Soong, Laszlo Halasz, Jessica Le Berichel, Maximilian M. Schaefer, Benoit Kloeckner, Raphaël Mattiuz, Matthew D. Park, Assaf Magen, Adam Marks, Meriem Belabed, Pauline Hamon, Theodore Chin, Leanna Troncoso, Juliana J. Lee, Kaili Fan, Dughan Ahimovic, Michael J. Bale, Kai Nie, Grace Chung, Darwin D’souza, Krista Angeliadis, Seunghee Kim-Schulze, Raja M. Flores, Andrew J. Kaufman, Florent Ginhoux, Jason D. Buenrostro, Steven Z. Josefowicz, Alexander M. Tsankov, Thomas U. Marron, Sai Ma, Brian D. Brown, and Miriam Merad.