Chemotherapy-induced activation of caspase-1 and IL-1α release by cancer cells remotely skews myelopoiesis to drive pro tumorigenic systemic neutrophil-dominant inflammation

  • Nat Commun. 2026 Apr 20;17(1):4724. doi: 10.1038/s41467-026-71471-3.
Stephen Qr Wong  #  1  2 ,  Kazukuni Hayashi  #  3 ,  Ethan J Subel  #  1  2 ,  Yung Hsing Huang  1 ,  Hongbo Gao  1  2 ,  Haley E Garcia  1 ,  Sophie J Porter  1 ,  Mustafa Karabicici  1 ,  Xen Ping Hoi  1  4 ,  Mark D Alonzo  1 ,  Armine Kasabyan  1 ,  Efrosini Tsouko  5 ,  Crystal S Shin  5 ,  Lisa Bouchier-Hayes  5 ,  Dimitrios Korentzelos  6 ,  Chen Chen  7 ,  Michael Brooks  1 ,  Zheng Yin  2 ,  Renil S Titus  1 ,  Lan Zhou  2  7 ,  Yinan Gong  1  2 ,  Yulin Li  2 ,  Stephen Tc Wong  2 ,  Ziad El-Zaatari  7 ,  Dharam Kaushik  1 ,  Raj Satkunasivam  1 ,  Fotis Nikolos  1 ,  Keith S Chan  8  9
Affiliations
  • 1. Department of Urology, Houston Methodist Research Institute, Houston, TX, USA.
  • 2. Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
  • 3. Department of Pathology, Stanford University, Stanford, CA, USA.
  • 4. Graduate Program in Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 5. Baylor College of Medicine, Houston, TX, USA.
  • 6. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 7. Department of Pathology, Houston Methodist Research Institute, Houston, TX, USA.
  • 8. Department of Urology, Houston Methodist Research Institute, Houston, TX, USA. [email protected].
  • 9. Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. [email protected].
  • # Contributed equally.
PMID: 42009646 DOI: 10.1038/s41467-026-71471-3
Abstract

While chemotherapy-induced tumor cell death is known to modulate the local immune landscape, its systemic impact on distant bone marrow-a site essential for immune cell maturation-remains underexplored. Here, we show that gemcitabine chemotherapy induces inflammatory caspase-1-dependent Pyroptosis in epithelial Cancer cells (epiCaspase-1). Despite its inflammatory nature, epiCaspase-1-mediated cell death is non-immunogenic. Clinically, elevated expression of an epiCaspase-1 gene signature correlates with worse patient outcomes. Mechanistically, epiCaspase-1 triggers the noncanonical release of IL-1α through NINJ1 lytic pores, remotely skewing bone marrow hematopoiesis towards granulocyte-monocyte progenitors and mature neutrophil output. This systemic reprogramming elevates the neutrophil-to-lymphocyte ratio (NLR) in both peripheral blood and the local tumor microenvironment. Pharmacological inhibition of Caspase-1 and IL-1α disrupts this cascade, normalizes hematopoiesis, and recalibrates NLR by promoting intratumoral CD8+ T cell infiltration and activation, ultimately enhancing chemotherapeutic efficacy. These findings challenge the assumption that inflammatory Pyroptosis is inherently immunogenic; instead, it can reshape systemic immune landscape towards a neutrophil-dominant inflammation in the chemotherapy context.

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