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

Sep 22, 2026

LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, yet the mechanisms are unclear. Using genetically engineered mouse models and human tumor samples, researchers show LKB1 loss increases LIF, activating a cancer cell–autonomous autocrine loop that drives infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Lifr deletion induces tumor plasticity and a Sox17+ dedifferentiated inflammatory state, while LIF neutralization eliminates this state and restores antitumor T cell responses, identifying LIF as a therapeutic target.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Introduction

Tumor microenvironment and immune interplay

Tumor cell evolution and immune impact

Significance

ReseaRch aRticle LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer Ray Pillai1,2,3, Ali Rashidfarrokhi2,4, Yuan Hao5, 6, Warren L. Wu2,4, Mariana C.S. Mancini2,7, Burcu Karadal-Ferrena2,8, Sofia G. Dimitriadoy2, Michael Cross2,4, Anna H. Yeaton2, 6, Shih Ming Huang2, Arjun Bhutkar9, Alberto M. Herrera10, Sahith Rajalingam2, Makiko Hayashi2, Kuan-lin Huang11, Eric Bartnicki4, 12, Anastasia-Maria Zavitsanou2,4, Ellie Ivanova2, Corrin Wohlhieter13, Sarah E. LeBoeuf2, Ting Chen14, Cynthia A. Loomis15, Ruth Kulicke16, Fred P. Davis16, Nicolas Stransky16, Gromoslaw Aleksander Smolen16, Jun-Chieh J. Tsay1,3, Fernando Moreira Simabuco17, Charles M. Rudin13, 18, Andre L. Moreira2, Kamal M. Khanna6, 12, Harvey I. Pass 19, Kwok-Kin Wong 14, Shohei Koide6,20, Aristotelis Tsirigos2, 5, Sergei B. Koralov2, 6, and Thales Papagiannakopoulos2, 6 LKB1 mutations in lung cancer promote an immunosuppressive tumor micro environment, 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. intRoduction There is a complex interplay between diverse cell types within the tumor microenvironment (TME) of lung adenocarcinomas (LUAD) which is composed of tumor cells, stromal cells, and immune populations (1, 2) . The interaction between immune cells and cancer cells plays a pivotal role in either inhibiting or facilitating tumor growth. Within the lung, the main tissue-resident immune population consists of alveolar macrophages (3), which are pivotal in maintaining lung homeostasis (4). In the setting of injury, infection, or cancer, bone marrow–derived immune populations, including neutrophils, monocyte-derived macrophages (3, 5, 6), and T cells, infiltrate the lung tissue. Whereas the importance of augmenting T cell–mediated antitumor immune responses 1Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York. 2Department of Pathology, New York University Grossman School of Medicine, New York, New York. 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, VA New York Harbor Healthcare System, New York, New York. 4Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York, New York. 5Applied Bioinformatics Laboratories, New York University Langone Health, New York, New York. 6Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York. 7Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, Brazil. 8Department of Basic Oncology, Hacettepe University, Ankara, Turkey. 9

FAQs

What role does LKB1 loss play in shaping the lung tumor microenvironment?

LKB1 loss drives high LIF expression that creates an immunosuppressive microenvironment by promoting infiltration of SiglecFHi neutrophils and Arg1+ interstitial macrophages.

How does LIF signaling contribute to tumor plasticity?

Autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state.

What is the effect of neutralizing LIF in LKB1 mutant lung cancer?

Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T cell responses.

Sep 22, 2026

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