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

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.

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Publication Details

Journal
Nature Communications
Published
2025-11-21
DOI
https://doi.org/10.1038/s41467-025-64839-4
Citations
2
Primary Topic
Redox biology and oxidative stress
Type
article
Field-Weighted Citation Impact
1.61

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article

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

Xingping Yang, Hélène Bellio, Aziza Aznague, Caroline Truntzer et al.
2 citations
Nature Communications
Redox biology and oxidative stress
1.61
article

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

Xingping Yang, Hélène Bellio, Aziza Aznague, Caroline Truntzer, David Rageot, Emeric Limagne, Nicolas Roussot, Anaïs Perrichet, Romain Aucagne, Cédric Rébé, François Ghiringhelli, Alfred Zippelius, Julie Lecuelle, Fanny Chalmin, Valentin Dérangère, Bertrand Routy, Lisa Nuttin, Pier Paolo Di Russo, Alis Ilie, Pierre Jacob, Titouan Huppé, Flavie Gaucher, Thibault Vernet, Marie Thiefin
article en
2 citations

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.

Nature CommunicationsVol. 16(1)
Inserm (FR), Université de Bourgogne (FR), University Hospital of Basel (CH), Centre Georges François Leclerc (FR), La Ligue Contre le Cancer (FR), Université Bourgogne Franche-Comté (FR), Fédération Francophone de Cancérologie Digestive (FR), Genomic and Immunotherapy Medical Institute (FR), Center for Translational Molecular Medicine (NL), Centre de recherche Translationnelle en Médecine moléculaire (FR), Laboratoire de Cristallographie et Sciences des Matériaux (FR), Université Bourgogne Europe (FR), Université de Montréal (CA)
Association pour la Recherche sur le Cancer, Agence Nationale de la Recherche, Université de Bourgogne, Institut National Du Cancer
Openalex Percentile: Top 14%
Redox biology and oxidative stress
1.61
DOIOpen Access PDFOpenAlex
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