Benjamin J. Solomon

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.

Geometric mean serum concentration-time profiles of rilvegostomig by dose (PK analysis set).

Patient disposition in Part A and Part B of ARTEMIDE-01.

Kaplan-Meier plot of PFS with rilvegostomig.

Inclusion and exclusion criteria for Parts A and B of ARTEMIDE-01 study.

Supplementary Methods and Materials.

Patient demographics and baseline disease characteristics in Part A by dose level.

Representativeness of study participants.

Summary of rilvegostomig safety profile in Part A by dose level.

Anti-drug antibody responses (immunogenicity analysis set).