STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment
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Abstract
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies.
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STK11 knockout was sufficient to induce an immune-suppressive environment in MC38 tumors.
“Additionally, STK11 knockout led to an increase in intratumoral MDSCs (Supplementary Fig. S1C), indicating that STK11 knockout was sufficient to induce an immune-suppressive environment in MC38 tumors in a manner consistent with STK11 loss-of-function in human tumors (8, 21).”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [8]
STK11-mutant tumors are characterized by lower T-cell infiltration than tumors wild-type for STK11.
“STK11-mutant tumors are characterized by lower T-cell infiltration (1, 7, 8), higher levels of immune-suppressive neutrophils (8), and low levels of antigen presentation (9, 10) compared with those wild-type for STK11, contributing to their immune evasive phenotype.”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [8]
STK11-mutant tumors are characterized by higher levels of immune-suppressive neutrophils than tumors wild-type for STK11.
“STK11-mutant tumors are characterized by lower T-cell infiltration (1, 7, 8), higher levels of immune-suppressive neutrophils (8), and low levels of antigen presentation (9, 10) compared with those wild-type for STK11, contributing to their immune evasive phenotype.”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [8]
Co-occurrence of STK11 deficiency promotes activation of proinflammatory cytokine production.
“Recent work has revealed co-occurring kelch like ECH associated protein 1 gene (KEAP1)/ nuclear factor erythroid 2, like 2 gene (NFE2L2) mutations as an independent negative prognostic factor regarding survival and response to platinum-based chemotherapy 15,24 and leading to dependence on glutaminolysis, whereas co-occurrence of serine/threonine kinase 11 deficiency promotes activation of pro”
From K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways (2019) · cites this paper as [25]
LKB1 inactivation epigenetically silences STING, which makes cells less responsive to cytosolic dsDNA buildup.
“LKB1 inactivation induces epigenetic repression of STING (also known as TMEM173), thus promoting insensitivity to cytosolic dsDNA accumulation136.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [136]
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Ahronian, L. G., Sahu, S., Zhang, M., Patel, A. S., Geng, K., Bhattacharya, R., Falchook, G. S., Goldman, J. W., Spira, A. I., Punekar, S. R., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-0998 · Cited by 9 · see citing works
“STK11 -mutant tumors are characterized by lower T-cell infiltration (1, 7, 8), higher levels of immune-suppressive neutrophils (8), and low levels of antigen presentation (9, 10) compared with those wild-type for STK11 , contributing to their immune evasive phenotype.”
Self-citation
- Authors
- Koyama, S., Akbay, E. A., Li, Y. Y., Aref, A. R., Skoulidis, F., Herter-Sprie, G. S., Buczkowski, K. A., Liu, Y., Awad, M. M., Denning, W. L., Diao, L., Wang, J., Parra-Cuentas, E. R., Wistuba, I. I., Soucheray, M., Thai, T., Asahina, H., Kitajima, S., Altabef, A., Cavanaugh, J. D., Rhee, K., Gao, P., Zhang, H., Fecci, P. E., Shimamura, T., Hellmann, M. D., Heymach, J. V., Hodi, F. S., Freeman, G. J., Barbie, D. A., Dranoff, G., Hammerman, P. S., & Wong, K.-K.
- Affiliations
- Brigham and Women's Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- University of California, San Francisco (US)
- Duke University (US)
- Loyola University Chicago (US)
- Memorial Sloan Kettering Cancer Center (US)
- Novartis (Switzerland) (CH)
- Corresponding author
- Dranoff, Glenn
- Wong, Kwok-Kin
- ORCID
- Koyama, Shohei
- Akbay, Esra A.
- Li, Yvonne Y.
- Aref, Amir R.
- Skoulidis, Ferdinandos
- Herter-Sprie, Grit S.
- Liu, Yan
- Awad, Mark M.
- Denning, Warren L.
- Diao, Lixia
- Wang, Jing
- Wistuba, Ignacio I.
- Soucheray, Margaret
- Thai, Tran
- Asahina, Hajime
- Kitajima, Shunsuke
- Gao, Peng
- Zhang, Haikuo
- Fecci, Peter E.
- Shimamura, Takeshi
- Hellmann, Matthew D.
- Heymach, John V.
- Hodi, F. Stephen
- Freeman, Gordon J.
- Barbie, David A.
- Dranoff, Glenn
- Hammerman, Peter S.
- Wong, Kwok-Kin
- Venue
- Cancer Research
- Published
- 2016-02-29
- Volume
- 76
- Issue
- 5
- Pages
- 999-1008
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4775354
- OpenAlex
- W2273119405
- Cited by
- 640
- References
- 39
- Citations by year
- 2026: 55 · 2025: 71 · 2024: 70 · 2023: 68 · 2022: 77 · 2021: 81 · 2020: 84 · 2019: 53 · 2018: 42 · 2017: 28 · 2016: 11
- FWCI
- 23.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation (Clinical Investigator Award)
- NCI (P50 CA090578)
- NIH/NCI (P01 CA120964, 5R01CA163896-04, 1R01CA195740-01, 5R01CA140594-07, 5R01CA122794-10, 5R01CA166480-04)
- Dana-Farber Cancer Institute
- American Cancer Society (Grant Number: SU2CAACR-DT17-15)
- Deutsche Forschungsgemeinschaft (HE 6897/1-1)
- Uniting Against Lung Cancer and American Cancer Society
- NIH (R01AI08995)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- STK11/LKB1, tumor suppressor inactivation, non-small cell lung cancer, KRAS mutation, neutrophil recruitment, tumor microenvironment, T cell exhaustion, inflammatory cytokines, interleukin-6, PD-L1, tumor-infiltrating lymphocytes, immune evasion, immunotherapy resistance
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Animals, Humans, Lung Neoplasms, Mutation, T-Lymphocytes, Cytokines, Lymphocytes, Tumor-Infiltrating, Protein Serine-Threonine Kinases, Neutrophil Infiltration, Mice, AMP-Activated Protein Kinases, Tumor Microenvironment, B7-H1 Antigen
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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