Complex I inhibition combined with TLR activation in the breast tumor microenvironment educates cytotoxic neutrophils

  • Sci Adv. 2025 Jul 11;11(28):eadu5915. doi: 10.1126/sciadv.adu5915.
John Heath  1  2  3 ,  Ryuhjin Ahn  4  5 ,  Valerie Sabourin  2 ,  Young Kyuen Im  2 ,  Sabrina Rezzara Richard  6 ,  Alva Annett  2 ,  Caitlynn Mirabelli  2  6 ,  Samantha Worme  2 ,  Sarah M Maritan  6  7 ,  Caitlyn Mourcos  7 ,  Anna Maria Lazaratos  7 ,  Elias Maldonado  2  6 ,  Yun Yun Shen  7 ,  Forest M White  4  5 ,  Claudia L Kleinman  2  8 ,  Peter M Siegel  1  6  7  9  10 ,  Josie Ursini-Siegel  1  2  6  9  10
Affiliations
  • 1. Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
  • 2. Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
  • 3. Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
  • 4. David H. Koch Institute for Integrative Cancer Research, Cambridge, MA, USA.
  • 5. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 6. Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • 7. Goodman Cancer Institute, McGill University, Montreal, QC, Canada.
  • 8. Department of Human Genetics, McGill University, Montreal, QC, Canada.
  • 9. Department of Medicine, McGill University, Montreal, QC, Canada.
  • 10. Department of Biochemistry, McGill University, Montreal, QC, Canada.
PMID: 40644540 DOI: 10.1126/sciadv.adu5915
Abstract

Although effective for immunologically hot tumors, immune checkpoint inhibitors minimally affect tumors that are not T cell inflamed, including breast Cancer. An alternate strategy to combat immune cold breast tumors may be to reeducate innate immunity. This study identifies strategies to skew neutrophils to acquire tumoricidal properties. Systemic Toll-like Receptor (TLR)-induced inflammation, concomitant with mitochondrial complex I inhibition in breast tumors, increases neutrophil cytotoxicity against breast Cancer cells and independently of CD8+ T cell immunity. These therapy-entrained neutrophils enhance secretory granule production, increasing expression of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase machinery and inducing a respiratory burst. Moreover, systemic administration of TLR agonists elevates nuclear factor κB signaling in neutrophils to increase production of secretory granule and NADPH Oxidase machinery components, whereas complex I inhibitors are required to potentiate oxidative damage. In summary, we describe a class of neutrophils, educated by the combined action of inflammatory mediators and metabolic inhibitors, having tumoricidal functions.

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