Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours

Samarth Hegde^{1

2}, Bruno Giotti^#^{1

3}, Brian Y Soong^#^{1

2}, Laszlo Halasz^{1

2}, Jessica Le Berichel^{1

2}, Maximilian M Schaefer^{1

2}, Benoit Kloeckner⁴, Raphaël Mattiuz^{1

2}, Matthew D Park^{1

2}, Assaf Magen¹, Adam Marks^{1

2

3

5}, Meriem Belabed^{1

2}, Pauline Hamon^{1

2}, Theodore Chin^{1

2}, Leanna Troncoso^{1

2}, Juliana J Lee⁶, Kaili Fan⁷, Dughan Ahimovic^{8

9}, Michael J Bale^{8

9}, Kai Nie^{1

2

10}, Grace Chung^{1

2

10}, Darwin D'souza^{1

2

10}, Krista Angeliadis^{1

2

10}, Seunghee Kim-Schulze^{1

2

10}, Raja M Flores^{5

11

12}, Andrew J Kaufman^{5

11

12}, Florent Ginhoux⁴, Jason D Buenrostro⁷, Steven Z Josefowicz^{8

9}, Alexander M Tsankov^{1

3

5}, Thomas U Marron^{1

2

3

5

11

12}, Sai Ma^{3

5}, Brian D Brown^{1

2

3

5}, Miriam Merad^{13

14

15

16}

Affiliations

¹ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Institut Gustave Roussy, INSERM U1015, Villejuif, France.
⁵ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Immunology, Harvard Medical School, Boston, MA, USA.
⁷ Department of Stem Cell and Regenerative Biology, Harvard Medical School, Boston, MA, USA.
⁸ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
⁹ Laboratory of Epigenetics and Immunity, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁰ The Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.
¹⁴ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.
¹⁵ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.
¹⁶ The Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.

^# Contributed equally.

PMID: 40931076
DOI: 10.1038/s41586-025-09493-y

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours

Samarth Hegde et al. Nature. 2025.

. 2025 Sep 10.

doi: 10.1038/s41586-025-09493-y. Online ahead of print.

Authors

Affiliations

¹ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Institut Gustave Roussy, INSERM U1015, Villejuif, France.
⁵ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Immunology, Harvard Medical School, Boston, MA, USA.
⁷ Department of Stem Cell and Regenerative Biology, Harvard Medical School, Boston, MA, USA.
⁸ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
⁹ Laboratory of Epigenetics and Immunity, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁰ The Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.
¹⁴ Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.
¹⁵ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.
¹⁶ The Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.

^# Contributed equally.

PMID: 40931076
DOI: 10.1038/s41586-025-09493-y

Abstract

Monocyte-derived macrophages (mo-macs) often drive immunosuppression in the tumour microenvironment (TME)¹ and tumour-enhanced myelopoiesis in the bone marrow fuels these populations². Here we performed paired transcriptome and chromatin accessibility analysis over the continuum of myeloid progenitors, circulating monocytes and tumour-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. We show that lung tumours prime accessibility for Nfe2l2 (NRF2) in bone marrow myeloid progenitors as a cytoprotective response to oxidative stress, enhancing myelopoiesis while dampening interferon response and promoting immunosuppression. NRF2 activity is amplified during monocyte differentiation into mo-macs in the TME to regulate stress and drive immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced the survival and immunosuppression of mo-macs in the TME, restoring natural killer and T cell anti-tumour immunity and enhancing checkpoint blockade efficacy. Our findings identify a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the lung TME and highlight the potential of early interventions to reprogram macrophage fate for improved immunotherapy outcomes.

PubMed Disclaimer

Conflict of interest statement

Competing interests: M.M. serves on the scientific advisory board and holds stock from Compugen Inc., Dynavax Inc., Innate Pharma Inc., Morphic Therapeutics, Asher Bio Inc., Dren Bio Inc., Nirogy Inc., Genenta Inc., Oncoresponse, Inc. and Owkin Inc. M.M. also serves on the ad hoc scientific advisory board of DBV Technologies Inc. and Genentech Inc., and on the foundation advisory board of Breakthrough Cancer. M.M. receives funding for contracted research from Genentech, Regeneron and Boehringer Ingelheim. T.U.M. has served on advisory and/or data safety monitoring boards for Rockefeller University, Regeneron Pharmaceuticals, Abbvie, Bristol-Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus and Astellas, and receives contracted grants from Regeneron, Bristol-Myers Squibb, Merck and Boehringer Ingelheim. The above interests are not directly relevant to this manuscript. The remaining authors declare no competing interests.

Update of

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.
Hegde S, Giotti B, Soong BY, Halasz L, Berichel JL, Magen A, Kloeckner B, Mattiuz R, Park MD, Marks A, Belabed M, Hamon P, Chin T, Troncoso L, Lee JJ, Ahimovic D, Bale M, Chung G, D'souza D, Angeliadis K, Dawson T, Kim-Schulze S, Flores RM, Kaufman AJ, Ginhoux F, Josefowicz SZ, Ma S, Tsankov AM, Marron TU, Brown BD, Merad M. Hegde S, et al. bioRxiv [Preprint]. 2024 Jun 28:2024.06.24.600383. doi: 10.1101/2024.06.24.600383. bioRxiv. 2024. Update in: Nature. 2025 Sep 10. doi: 10.1038/s41586-025-09493-y. PMID: 38979166 Free PMC article. Updated. Preprint.

References

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1. Swann, J. W., Olson, O. C. & Passegue, E. Made to order: emergency myelopoiesis and demand-adapted innate immune cell production. Nat. Rev. Immunol. 24, 596–613 (2024). - PubMed - DOI
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Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours

Affiliations

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References