# Selective inhibition of canonical STAT3 signaling suppresses K-ras mutant lung tumorigenesis and reinvigorates anti-tumor immunity

## TL;DR

A new drug inhibits a key inflammatory pathway in a type of hard-to-treat lung cancer, reducing tumor growth and boosting immune response.

## Contribution

The study demonstrates that selective inhibition of STAT3 signaling can suppress K-ras mutant lung cancer and enhance anti-tumor immunity.

## Key findings

- TTI-101 treatment reduced tumor burden and increased immune cell infiltration in a mouse model of K-ras mutant lung cancer.
- STAT3 inhibition was linked to improved immune activation and better survival in patients with low STAT3 expression.
- Transcriptional profiling showed B cell signaling enrichment and anti-tumor skewing in the tumor microenvironment.

## Abstract

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).

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).

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.

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.