Selective Inhibition of Canonical STAT3 Signaling Suppresses K-ras Mutant Lung Tumorigenesis and Reinvigorates Anti-tumor Immunity

Authors

Michael J Clowers
Zahraa Rahal
Sung-Nam Cho
Avantika Krishna
Bo Yuan
Leticia G Hamana Zorrilla
T Kris Eckols
Moses M Kasembeli
Samuel Liu
Stephen Peng
Marco Ramos-Castaneda
Annamarie L Thompson
Carlos Ignacio Rodriguez Reyna
Katherine E Larsen
Maria T Grimaldo
Shanshan Deng
Nastaran Karimi
Cody Chou
Walter V Velasco
Melody Zarghooni
Sayan Alekseev
Luisa M Solis Soto
Edwin J Ostrin
Humam Kadara
Suhendan Ekmekcioglu
David J Tweardy
Seyed Javad Moghaddam

Publication Date

1-1-2025

Journal

Frontiers in Immunology

Abstract

Introduction: K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-treat cancer subtype in which chronic inflammation pervades the tumor immune microenvironment (TIME). Pro-inflammatory pathways dampen the response to treatments, including immune checkpoint inhibitors, necessitating therapies that target this inflammatory signaling network in the TIME. One of the lynchpins of chronic inflammation in KM-LUAD is signal transducer and activator of transcription 3 (STAT3).

Methods: Here, we tested the anti-tumor and early immunotherapeutic efficacy of TTI-101, a selective small-molecule inhibitor of canonical STAT3 signaling, in a K-rasG12D mutant lung cancer mouse model (CC-LR).

Results: Treatment of CC-LR mice with TTI-101 resulted in reduced tumor burden while increasing dendritic cell (DC) and T helper 1 (Th1) infiltration into the TIME. TTI-101 treatment decreased pY-STAT3 expression in tumors with accompanying increases in several NF-κB anti-tumor target genes including CXCL9, a chemokine for primed T cells. Transcriptional profiling of the TIME revealed improved immune activation and anti-tumor skewing, as well as B cell signaling enrichment. Analysis of human LUAD data demonstrated negative correlations between STAT3 and Th1/DC infiltration, with DC infiltration also conferring improved survival in LUAD patients with low STAT3.

Discussion: Our results highlight the importance of STAT3 in driving early tumorigenesis and offer a preventative treatment window for high-risk individuals and patients with early-stage KM-LUAD.

Keywords

STAT3 Transcription Factor, Animals, Lung Neoplasms, Mice, Signal Transduction, Tumor Microenvironment, Mutation, Humans, Adenocarcinoma of Lung, Proto-Oncogene Proteins p21(ras), Disease Models, Animal, Dendritic Cells, Carcinogenesis, Female, DC, K-ras, LUAD, Th1, stat3, tumor-promoting inflammation.

DOI

10.3389/fimmu.2025.1575181

PMID

40356899

PMCID

PMC12066534

PubMedCentral® Posted Date

4-28-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes