New research from the Icahn School of Medicine at Mount Sinai, published on September 10, 2025, in the prestigious journal Nature, challenges the prevailing understanding of how lung tumors evade the immune system. Until now, it was widely believed that immune suppression in the tumor microenvironment occurred after immune cells had migrated to the tumor site. However, this groundbreaking study reveals that lung tumors initiate a complex reprogramming of immune cells much earlier—directly within the bone marrow where these cells originate. This discovery not only reshapes fundamental concepts in cancer immunology but also opens new avenues for enhancing the effectiveness of immunotherapies currently used in clinical settings.
Immunotherapy has revolutionized cancer treatment by leveraging the patient’s own immune system to attack malignant cells. Despite its promise, the success of immunotherapies in solid tumors like non-small cell lung cancer (NSCLC) remains limited. A significant hurdle is the infiltration of pro-tumoral macrophages—immune cells that instead of combating cancer, help suppress the antitumor immune response. These macrophages create an immunosuppressive microenvironment, aiding tumor growth and survival. Prior assumptions held that such macrophages adopted their pro-cancer roles only after arriving at the tumor. The new findings overturn this idea by tracing the origin of this immune subversion back to the bone marrow, where macrophage precursors undergo critical changes.
Employing cutting-edge single-cell genomics and lineage-tracing technologies, the researchers mapped the developmental trajectory of bone marrow myeloid progenitor cells, the precursors to macrophages. Their analyses uncovered that tumors broadcast signals that deliver a “first hit” to these progenitor cells in the bone marrow. This initial exposure biases the developing immune cells toward an immunosuppressive phenotype even before they infiltrate the tumor. Later, once in the tumor microenvironment, a “second hit” acts as a catalyst that locks these macrophages into their pro-tumoral functions. This two-step model represents a paradigm shift in our understanding of immune cell education by cancer.
Dr. Samarth Hegde, the study’s lead author, highlights that the temporal aspect of immune suppression had been misunderstood for decades. Observing that immune cells are preconditioned within the bone marrow demands a radical rethink of therapeutic strategies. Traditional approaches focus predominantly on the tumor microenvironment, attempting to re-educate or inhibit macrophages after they have already entrenched themselves among cancer cells. This study suggests that such attempts might be inherently limited. Targeting the progenitor cells prior to their arrival at the tumor could prevent them from becoming immunosuppressive in the first place, thus preserving the immune system’s capacity to mount effective anticancer responses.
One of the most promising molecular candidates identified in this reprogramming process is NRF2, a transcription factor fundamentally involved in cellular stress responses and redox homeostasis. The research team discovered that NRF2 activity is modulated in bone marrow progenitor cells exposed to tumor-derived inflammatory signals, rewiring these cells’ genetic programs. This NRF2-driven reprogramming becomes fully operational when the progenitors differentiate into tumor-infiltrating macrophages, promoting immune suppression and tumor progression in both human patients and mouse models. Crucially, inhibiting NRF2—either through genetic manipulation or experimental pharmacological agents—significantly reduced the formation of suppressive macrophages and revitalized antitumor immunity in preclinical experiments.
Miriam Merad, MD, PhD, senior corresponding author and Chair of Immunology and Immunotherapy at Mount Sinai, emphasizes the translational potential of these findings. By targeting NRF2 signaling in bone marrow progenitors, it might be possible to halt the supply line of immunosuppressive macrophages at its source, essentially cutting off the tumor’s capacity to subvert the immune system. “Current immunotherapies largely address the tumor itself but fail to consider the precursor immune cells’ prior ‘education,’” Dr. Merad notes. “Early intervention at the progenitor stage could dramatically improve the durability of treatment responses and possibly reduce relapse rates.”
Additionally, this newly revealed mechanism of immune cell manipulation by tumors offers a compelling opportunity for diagnostic innovation. Since the reprogrammed myeloid progenitors circulate in the bloodstream before differentiating, blood-based tests could detect these “pre-programmed” immune cells, facilitating earlier diagnosis and enabling timely therapeutic intervention. Such liquid biopsies would mark a significant advance in personalized medicine, allowing clinicians to monitor immune cell states during treatment and remission with unprecedented precision.
The implications of this research extend well beyond lung cancer. The investigators plan to explore whether similar genetic and epigenetic mechanisms govern immune cell progenitor reprogramming in other malignancies and chronic inflammatory diseases such as aging, obesity, and atherosclerosis. These conditions often share dysregulated immune responses, and understanding the underlying molecular controls, including NRF2 signaling, may reveal new treatment opportunities. Moreover, aberrant immune cell proliferation outside of the bone marrow—called extramedullary hematopoiesis—is observed in some cancers, and the team aims to investigate if comparable molecular programs are at play there as well.
A critical future direction involves elucidating how NRF2 and related pathways influence the metabolic reprogramming of immune cells. Tumors are known to manipulate cellular metabolism to evade immunity, and dissecting these interactions at the molecular level may clarify how suppressive macrophages gain their functional phenotype. This could lead to novel metabolic interventions that complement existing immunotherapies, creating multi-pronged strategies to outsmart cancer.
The publication titled “Myeloid Progenitor dysregulation fuels immunosuppressive macrophages in tumors” represents a landmark achievement in cancer immunology. By highlighting how tumors manipulate immune cells from their earliest developmental stages, it provides a blueprint for the next generation of cancer therapies focused on the immune system’s origins rather than its endpoints. This foundational work not only advances scientific understanding but also heralds a promising translational leap toward more effective and durable treatment regimens for patients battling lung cancer and potentially other challenging diseases.
This discovery underscores the critical role of interdisciplinary collaboration and advanced technologies in unraveling the complexity of cancer biology. The team’s integration of genomics, immunology, and translational medicine exemplifies the frontier of precision immunology research, making Mount Sinai a leader in tackling the most stubborn challenges in oncology.
Subject of Research: Cells
Article Title: Myeloid Progenitor dysregulation fuels immunosuppressive macrophages in tumors
News Publication Date: 10-Sep-2025
Web References: https://www.nature.com/articles/s41586-025-09493-y
References: DOI 10.1038/s41586-025-09493-y
Keywords: Cancer immunotherapy
Tags: bone marrow immune cell reprogrammingcancer immunology breakthroughsenhancing immunotherapy effectivenessgroundbreaking cancer research findingsimmune system evasion strategiesimmunotherapy challenges in solid tumorslung cancer immune responsemacrophage infiltration in cancernon-small-cell lung cancer immunotherapypro-tumoral macrophages roletumor growth and survival mechanismstumor microenvironment immune suppression
