Cancer cell-derived IL-1β reverses chemo-immunotherapy resistance in non-small cell lung cancer

Anaïs Perrichet, Julie Lecuelle, Emeric Limagne, Marie Thiefin, Hélène Bellio, Pierre Jacob, Romain Aucagne, Aziza Aznague, Pauline Russo, Flavie Gaucher, Nicolas Roussot, Xingping Yang, Thibault Vernet, Lisa Nuttin, Alis Ilie, David Rageot, Valentin Derangère, Titouan Huppe, Alfred Zippelius, Bertrand Routy, Caroline Truntzer, Fanny Chalmin, François Ghiringhelli () and Cédric Rébé ()
Additional contact information
Anaïs Perrichet: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Julie Lecuelle: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Emeric Limagne: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Marie Thiefin: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Hélène Bellio: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Pierre Jacob: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Romain Aucagne: Université de Bourgogne Europe
Aziza Aznague: Université de Bourgogne Europe
Pauline Russo: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Flavie Gaucher: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Nicolas Roussot: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Xingping Yang: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Thibault Vernet: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Lisa Nuttin: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Alis Ilie: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
David Rageot: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Valentin Derangère: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Titouan Huppe: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Alfred Zippelius: University Hospital Basel, Cancer Immunology, Department of Biomedicine
Bertrand Routy: University of Montreal Research Center (CRCHUM)
Caroline Truntzer: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Fanny Chalmin: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
François Ghiringhelli: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform
Cédric Rébé: Centre Régional De Lutte Contre Le Cancer Georges-François Leclerc, Cancer Biology Transfer Platform

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Many non-small cell lung cancer (NSCLC) patients remain unresponsive to the current standard of care, which includes chemotherapy and immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies. While interleukin (IL)-1β is known to promote lung cancer growth in humans and mice, we show here that IL-1β administration or overexpression overcomes resistance to classical chemo-immunotherapy (cisplatin/pemetrexed/anti-PD-1) in mouse lung cancer models. The antitumor effects of IL-1β rely on cancer cell-derived CXCL10 which mediates CD8 T cell recruitment at the tumor site. In lung cancer cells, Thioredoxin Interacting Protein (TXNIP) induces mitochondrial DNA (mtDNA) release in the cytosol, activating Absence in Melanoma 2 (AIM2) inflammasome, which subsequently triggers IL-1β and CXCL10 secretion, thereby reversing chemo-immunotherapy resistance. The clinical relevance of our findings is supported by the transcriptomic analysis of patient tumors, showing that high expression of IL1B, IL1R1, AIM2 and/or TXNIP is associated with better response to immunotherapy in NSCLC patients. Additionally, drug screening identifies MEK and MDM2 inhibitors as inducers of TXNIP expression capable of reversing resistance to chemo-immunotherapy. This study highlights a positive role of IL-1β in lung cancer treatment and suggests that enhancing IL-1β production at the tumor site can overcome resistance to chemo-immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-64839-4

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