Language

English

Publication Date

4-20-2026

Journal

Nature Communications

DOI

10.1038/s41467-026-71471-3

PMID

42009646

PMCID

PMC13216336

PubMedCentral® Posted Date

4-20-2026

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Interleukin-1alpha, Neutrophils, Humans, Caspase 1, Myelopoiesis, Animals, Cell Line, Tumor, Inflammation, Tumor Microenvironment, Mice, Pyroptosis, Female, Carcinogenesis, CD8-Positive T-Lymphocytes

Published Open-Access

yes

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