# Smoking‐Induced STC2+ Tumor Cells Drive Tumor‐Vascular Crosstalk in Laryngeal Squamous Cell Carcinoma via Spatial and Single‐Cell Transcriptomics

## TL;DR

Smoking promotes laryngeal cancer spread by activating a specific cell signaling pathway that increases blood vessel permeability and metastasis.

## Contribution

The study reveals a novel nicotine-driven pathway involving STC2 and ITGA5 that mediates tumor-vascular interactions in smoking-associated LSCC.

## Key findings

- STC2 and ITGA5 are identified as smoking-associated prognostic markers in laryngeal squamous cell carcinoma.
- Nicotine activates the CHRNA5–JAK2/STAT3 axis to drive STC2 transcription, which upregulates TGFBI and interacts with endothelial ITGA5 to increase vascular permeability.
- STC2 knockdown disrupts cytoskeletal dynamics and epithelial polarity restoration, impairing tumor progression.

## Abstract

Smoking‐associated laryngeal squamous cell carcinoma (LSCC) is characterized by high metastatic potential and poor prognosis. However, the underlying molecular mechanisms remain insufficiently understood. This study utilized single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics to explore the heterogeneity of the tumor microenvironment in smoking‐associated LSCC. Thirteen distinct cellular subpopulations within the tumor microenvironment are identified, with STC2 and ITGA5 emerging as smoking‐associated prognostic markers. STC2 exhibited bifurcated differentiation within tumor epithelial cells, categorized as Tumor_C1 and Tumor_C2. The two subtypes are linked to vascular permeability and DNA replication pathways, respectively. Mechanistically, nicotine activated the JAK2/STAT3 signaling pathway through CHRNA5, resulting in direct STAT3 binding to the STC2 promoter and modulation of its transcription. STC2 subsequently upregulated TGFBI, which interacted with ITGA5 on endothelial cells, regulating vascular permeability and facilitating hematogenous dissemination of LSCC cells. Furthermore, STC2 knockdown altered F‐actin cytoskeletal dynamics by modulating small GTPase signaling, impairing filopodia formation and epithelial polarity restoration. This study elucidates the tumor–endothelial interactions mediated by STC2 and ITGA5 in smoking‐associated LSCC, emphasizing their roles in tumor progression and vascular permeability. These findings suggest potential prognostic biomarkers and therapeutic targets to improve the clinical management of smoking‐associated LSCC.

This study identifies a smoking‐induced mechanism in LSCC whereby nicotine activates the CHRNA5–JAK2/STAT3 axis to drive STC2 transcription. STC2 upregulates TGFBI, which interacts with endothelial ITGA5 to regulate vascular permeability and promote metastasis. These findings highlight the STC2–TGFBI–ITGA5 axis as a critical mediator of tumor–endothelial crosstalk and a potential therapeutic target in smoking‐associated LSCC.