# DMNQ induces ferroptosis and augments the efficacy of anti-PD-L1 immunotherapy in gastric cancer via the STAT3/SLC1A4 axis to mediate cysteine metabolism reprogramming

## TL;DR

DMNQ causes cell death in stomach cancer cells and improves immunotherapy by targeting a specific pathway that controls cysteine metabolism.

## Contribution

DMNQ induces ferroptosis and enhances anti-PD-L1 immunotherapy via the STAT3/SLC1A4 axis in gastric cancer.

## Key findings

- DMNQ inhibits STAT3 phosphorylation and transcriptional activity to induce ferroptosis in gastric cancer cells.
- The STAT3/SLC1A4 axis regulates cysteine uptake and enhances anti-PD-L1 immunotherapy efficacy.
- DMNQ boosts anti-tumor effects when combined with anti-PD-L1 immunotherapy in gastric cancer.

## Abstract

Ferroptosis plays an essential role in tumor progression. Therapeutic agents targeting ferroptosis emerge as a novel strategy for cancer treatment. Abnormal amino acid metabolism can control ferroptosis sensitivity in cancer cells, and lead to the deficiency or accumulation of specific products in the tumor microenvironment (TME). Here, we demonstrated that 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced growth inhibition in gastric cancer cell lines, primary gastric cancer mouse models, and patient-derived tumor organoids. DMNQ exerted ferroptosis inducing effects by inhibiting STAT3 phosphorylation and transcriptional activity. Importantly, the STAT3/SLC1A4 axis regulated cysteine uptake, tumor killing by T cells and the efficacy of anti-PD-L1 immunotherapy. Collectively, our findings revealed a critical mechanism by which DMNQ exerts a significant anti-cancer role in gastric cancer through increasing ferroptosis to enhance cancer immunotherapy and may provide a novel therapeutic strategy for gastric cancer.

•DMNQ induces ferroptosis in gastric cancer cells by targeting the SH2 domain of STAT3 and inhibiting its transcriptional activity.•DMNQ reprograms cysteine metabolism through STAT3/SLC1A4 axis.•STAT3/SLC1A4 axis regulates ferroptosis, tumor killing by T cells and the efficacy of anti-PD-L1 immunotherapy in gastric cancer.•DMNQ boosts anti-tumor effects with anti-PD-L1 immunotherapy.

DMNQ induces ferroptosis in gastric cancer cells by targeting the SH2 domain of STAT3 and inhibiting its transcriptional activity.

DMNQ reprograms cysteine metabolism through STAT3/SLC1A4 axis.

STAT3/SLC1A4 axis regulates ferroptosis, tumor killing by T cells and the efficacy of anti-PD-L1 immunotherapy in gastric cancer.

DMNQ boosts anti-tumor effects with anti-PD-L1 immunotherapy.