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

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

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.

Figures
Products