Complement-driven NETosis mediates immunotherapy resistance in STK11 -mutant lung adenocarcinoma

PURPOSE: Lung adenocarcinomas (LUADs) harboring concurrent mutations in KRAS and STK11 define a clinically aggressive subgroup characterized by primary resistance to immune checkpoint inhibitors (ICIs). In contrast, KRAS/TP53 co-mutant tumors typically exhibit an inflamed tumor microenvironment (TME) and improved responsiveness to immunotherapy. The mechanisms underlying immune evasion in KRAS/STK11-mutant LUADs remain incompletely understood. EXPERIMENTAL DESIGN: We assembled a multicenter cohort of human LUAD specimens and performed integrative genomic and immunophenotypic analyses to dissect the TME of KRAS/STK11 (KS) and KRAS/TP53 (KP) co-mutant tumors. RESULTS: We identify neutrophil extracellular trap (NET) formation as a defining feature of KS tumors, associated with neutrophil enrichment and reduced CD8⁺ T-cell infiltration. Using immunocompetent Kras-mutant murine models, we demonstrate that Stk11 loss promotes NETosis through activation of the complement C5a-C5aR1 axis, resulting in an immunosuppressive TME and resistance to PD-1/PD-L1 blockade. Pharmacologic inhibition of C5a signaling suppresses NETosis, reduces tumor growth, and restores T-cell infiltration in KS tumors. CONCLUSIONS: Our findings uncover NETosis as a key mechanism of immune escape in KRAS/STK11-mutant LUADs and identify the C5a-C5aR1 pathway as a therapeutically actionable vulnerability to overcome immunotherapy resistance in this patient population. These findings provide a rationale for biomarker-driven clinical strategies targeting the complement pathway in patients with STK11-mutant lung adenocarcinoma.

Authors

Institutions

Publication Details

Journal
Clinical Cancer Research
Published
2026-11-03
DOI
https://doi.org/10.1158/1078-0432.ccr-26-1792
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Complement-driven NETosis mediates immunotherapy resistance in STK11 -mutant lung adenocarcinoma

Luis M. Montuenga, Fernando Lecanda, Daniel Ajona, Leeat Keren et al.
Clinical Cancer Research
Cancer Immunotherapy and Biomarkers
article

Complement-driven NETosis mediates immunotherapy resistance in STK11 -mutant lung adenocarcinoma

Luis M. Montuenga, Fernando Lecanda, Daniel Ajona, Leeat Keren, Gavin Michael Wright, Javier Hernández‐Losa, María D. Lozano, Ignacio Melero, Ramon Amat, Carlos E. de Andrea, Jose Ignacio Echeveste, Juan Dubrot, Benjamin Solomon, Juan Pablo de-Torres, Rubén Pı́o, Álvaro López‐Janeiro, Álvaro Teijeira, Cristina Sainz, Ana Remírez, Allan Argueta, Enriqueta Felip, Valerio Perna, María Rodríguez
article en

Abstract

PURPOSE: Lung adenocarcinomas (LUADs) harboring concurrent mutations in KRAS and STK11 define a clinically aggressive subgroup characterized by primary resistance to immune checkpoint inhibitors (ICIs). In contrast, KRAS/TP53 co-mutant tumors typically exhibit an inflamed tumor microenvironment (TME) and improved responsiveness to immunotherapy. The mechanisms underlying immune evasion in KRAS/STK11-mutant LUADs remain incompletely understood. EXPERIMENTAL DESIGN: We assembled a multicenter cohort of human LUAD specimens and performed integrative genomic and immunophenotypic analyses to dissect the TME of KRAS/STK11 (KS) and KRAS/TP53 (KP) co-mutant tumors. RESULTS: We identify neutrophil extracellular trap (NET) formation as a defining feature of KS tumors, associated with neutrophil enrichment and reduced CD8⁺ T-cell infiltration. Using immunocompetent Kras-mutant murine models, we demonstrate that Stk11 loss promotes NETosis through activation of the complement C5a-C5aR1 axis, resulting in an immunosuppressive TME and resistance to PD-1/PD-L1 blockade. Pharmacologic inhibition of C5a signaling suppresses NETosis, reduces tumor growth, and restores T-cell infiltration in KS tumors. CONCLUSIONS: Our findings uncover NETosis as a key mechanism of immune escape in KRAS/STK11-mutant LUADs and identify the C5a-C5aR1 pathway as a therapeutically actionable vulnerability to overcome immunotherapy resistance in this patient population. These findings provide a rationale for biomarker-driven clinical strategies targeting the complement pathway in patients with STK11-mutant lung adenocarcinoma.

Clinical Cancer Research
Hebron University (PS), Peter MacCallum Cancer Centre (AU), St Vincent's Hospital Melbourne (AU), American Committee for the Weizmann Institute of Science (US), Vall d'Hebron Institut de Recerca (ES), Navarre Institute of Health Research (ES), Vall d'Hebron Hospital Universitari (ES), Clinica Universidad de Navarra (ES), Centro de Investigación Médica Aplicada (ES), Universidad de Navarra (ES), Chartered Institute of Management Accountants (GB)
Openalex Percentile: Top 17%
Cancer Immunotherapy and Biomarkers
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon