Chemotherapy-induced activation of caspase-1 and IL-1α release by cancer cells remotely skews myelopoiesis to drive pro tumorigenic systemic neutrophil-dominant inflammation
Date: | April 20, 2026 |
PMCID: | |
Category: | N/A |
Authors: | Stephen Qr Wong, Kazukuni Hayashi, Ethan J Subel, Yung Hsing Huang, Hongbo Gao, Haley E Garcia, Sophie J Porter, Mustafa Karabicici, Xen Ping Hoi, Mark D Alonzo, Armine Kasabyan, Efrosini Tsouko, Crystal S Shin, Lisa Bouchier-Hayes, Dimitrios Korentzelos, Chen Chen, Michael Brooks, Zheng Yin, Renil S Titus, Lan Zhou, Yinan Gong, Yulin Li, Stephen Tc Wong, Ziad El-Zaatari, Dharam Kaushik, Raj Satkunasivam, Fotis Nikolos, Keith S Chan |
Abstract: |
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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.
Acknowledgements:
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.
The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:
Project Number: | Awardee Organization |
U54CA274374 | Fred Hutchinson Cancer Center |
U54CA274375 | Houston Methodist Research Institute |
U54CA274370 | Johns Hopkins University |
U54CA274371 | UT MD Anderson Cancer Center |
U54CA274367 | Vanderbilt University Medical Center |
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