LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in <i>LKB1</i> -Mutant Lung Cancer

LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression. SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.

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Publication Details

Journal
Cancer Discovery
Published
2026-04-20
DOI
https://doi.org/10.1158/2159-8290.cd-25-0470
Primary Topic
Cytokine Signaling Pathways and Interactions
Type
article
Field-Weighted Citation Impact
0.00

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article

LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1 -Mutant Lung Cancer

Fred P. Davis, Sofia Dimitriadoy, Makiko Hayashi, Ruth Kulicke et al.
Cancer Discovery
Cytokine Signaling Pathways and Interactions
article

LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1 -Mutant Lung Cancer

Fred P. Davis, Sofia Dimitriadoy, Makiko Hayashi, Ruth Kulicke, Alberto Herrera, Anna Yeaton, Kwok‐Kin Wong, Gromoslaw A. Smolen, Shohei Koide, Kuan‐lin Huang, Kamal Mohan Khanna, Jun-Chieh James Tsay, André L. Moreira, Mariana Camargo Silva Mancini, Cynthia A. Loomis, Shih Ming Huang, Sarah E. LeBoeuf, Charles M. Rudin, Ellie Ivanova, Aristotelis Tsirigos, Ray Pillai, Sahith Rajalingam, Nicolas Stransky, Thales Papagiannakopoulos, Fernando Moreira Simabuco, Eric Bartnicki, Burcu Karadal-Ferrena, Sergei B. Koralov, Harvey I. Pass, Ali Rashidfarrokhi, Corrin Wohlhieter, Arjun Bhutkar, Ting Chen
article en

Abstract

LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression. SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.

Cancer Discovery
Memorial Sloan Kettering Cancer Center (US), Universidade Estadual de Campinas (UNICAMP) (BR), Cornell University (US), VA NY Harbor Healthcare System (US), NYU Langone Health (US), Celsius Therapeutics (United States) (US), Center for Genomic Science (IT), New York University (US), Massachusetts Institute of Technology (US), Hacettepe University (TR), Universidade Federal de São Paulo (BR)
American Cancer Society, Stony Wold-Herbert Fund, LEO Fondet, National Institutes of Health, Centros de Pesquisa, Inovação e Difusão, Fundação Amazônia Paraense de Amparo à Pesquisa
Good health and well-being
Openalex Percentile: Top 18%
Cytokine Signaling Pathways and Interactions
DOIOpen Access PDFOpenAlex
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