# Neoadjuvant Chemotherapy With Cisplatin Up‐Regulates GSDMD to Enhance Oral Squamous Cell Carcinoma Metastasis Through MMP14‐Mediated EMT Activation

## TL;DR

Low-dose cisplatin chemotherapy increases GSDMD in oral cancer, promoting metastasis, but using nanoparticles to silence GSDMD can reduce this effect.

## Contribution

Identifies GSDMD as a novel mediator of cisplatin-induced metastasis in oral cancer and proposes NP-mediated GSDMD silencing as a treatment strategy.

## Key findings

- Low-dose cisplatin promotes OSCC migration, invasion, and lymph node metastasis via GSDMD upregulation.
- GSDMD interacts with MMP14 to activate EMT without pyroptosis, driving cancer metastasis.
- Nanoparticle-delivered siGSDMD effectively inhibits tumor growth and metastasis in vivo.

## Abstract

Neoadjuvant chemotherapy has been widely used for the treatment of solid tumors. However, clinical observations have shown that patients with oral squamous cell carcinoma (OSCC) who are receiving neoadjuvant chemotherapy with cisplatin still face issues such as a poor lymph node response and even lymph node progression, but the underlying mechanisms remain unidentified. In this work, it is found that low‐dose cisplatin promoted oral squamous cell carcinoma migration, invasion and lymph node metastasis, and gasdermin D (GSDMD) is identified as a potential regulator. GSDMD interacted with MMP14, promoting its expression and epithelial‒mesenchymal transition (EMT) activation without activating pyroptosis. Moreover, pH‐responsive nanoparticles (NPs) for the systemic delivery of a GSDMD siRNA (siGSDMD) is developed and showed that this NP‐delivered siGSDMD can effectively inhibit OSCC tumor growth and metastasis via the efficient silencing of GSDMD expression in vivo. This findings indicate that GSDMD can be a biomarker to predict the prognosis of OSCC patients receiving neoadjuvant chemotherapy and that NP‐mediated GSDMD silencing can be a promising strategy for the treatment of patients with advanced OSCC receiving neoadjuvant chemotherapy with cisplatin.

Oral squamous cell carcinoma cells exhibit upregulated expression of GSDMD upon exposure to low‐dose cisplatin chemotherapy, which subsequently interacts with MMP14 through its N‐terminal domain, activating the epithelial‒mesenchymal transition (EMT) process and promoting the lymph node metastasis of oral squamous cell carcinoma. Targeted delivery of siGSDMD via NPs can inhibit the cisplatin‐induced metastasis of oral squamous cell carcinoma.