Lung Cancer Alters Immune Cell Development in Bone Marrow, Impairing the Body's Defense Mechanisms

Recent research from the Icahn School of Medicine at Mount Sinai has revealed that lung tumors do more than just evade the immune system; they actively reshape it at its origin. Published in the September 10, 2025, issue of Nature, the study demonstrates that tumors can rewire immune cells within the bone marrow before these cells even reach the tumor site. This early reprogramming biases immune progenitors toward supporting cancer growth, providing a potential new target to strengthen immunotherapy outcomes.

Immunotherapy has revolutionized treatment for many cancers by mobilizing the body's defenses. However, in solid tumors such as non-small cell lung cancer (NSCLC), its effectiveness is often hindered by immune-suppressing macrophages. Traditionally, scientists believed these macrophages turned problematic only after reaching the tumor. Now, new evidence suggests otherwise.

Using advanced single-cell genomic techniques, researchers mapped the development of bone marrow myeloid progenitor cells—the precursors to macrophages. They found that signals from the tumor deliver a 'first hit' to these cells, altering their course and predisposing them to adopt pro-tumor functions. A subsequent 'second hit' within the tumor environment cements their immune-suppressive role.

"This work shifts our understanding of the timing of immune suppression in cancer," said Dr. Samarth Hegde, lead author and postdoctoral fellow at Mount Sinai. "We see that immune cells are already being reprogrammed in the bone marrow long before they arrive at the tumor. Targeting this process early, during cell development, could prevent immune suppression altogether."

A key protein highlighted in the study is NRF2, which helps cells manage stress. The researchers observed that tumor-associated cues activate NRF2 in progenitor cells, promoting their transformation into macrophages that suppress immune responses. Experimental blocking of NRF2 reduced the formation of these immunosuppressive macrophages and enhanced the immune attack against tumors in preclinical models.

These findings provide a compelling rationale for combining NRF2 inhibitors with existing immunotherapies. Intervening earlier in the immune cell development process may prevent the tumor from creating a protective shield of immune-suppressing cells, thereby improving treatment success.

Moreover, the researchers propose that blood-based tests detecting pre-programmed immune cells could enable earlier diagnosis and monitoring of NSCLC, offering new avenues for patient management. The team is also investigating whether similar genetic switches influence immune cell behavior in other cancers and inflammatory conditions such as aging, obesity, and atherosclerosis.

This groundbreaking research offers a new perspective on cancer immunology, emphasizing the importance of early immune cell reprogramming. Ultimately, this could lead to novel strategies that rewire the immune system to better combat cancer from its source.