Spatial Transcriptomics Unveils Landscape of Resistance to Concurrent Chemo-Radiotherapy in Hypopharyngeal Squamous...

Hypopharyngeal squamous cell carcinoma (SCC) is an aggressive malignancy with a poor prognosis, particularly in advanced stages. Concurrent chemoradiotherapy (CCRT) is frequently employed to preserve the larynx, but resistance to CCRT remains a significant clinical challenge. Understanding the tumor microenvironment (TME) in CCRT-resistant cases is crucial for identifying predictive biomarkers and developing targeted therapies to improve outcomes.

This study analyzed tissue samples from patients with advanced hypopharyngeal SCC who were either resistant to CCRT or had not received CCRT. Spatial transcriptomics (ST) was used to explore the spatial molecular signatures within the TME of these samples, focusing on the interactions between immune cells and malignant cells.

We identified six distinct cellular clusters in the hypopharyngeal SCC tissues, with a signature cluster more prominently present in CCRT-resistant samples. The SPP1 gene was significantly overexpressed in these samples, specifically in macrophages, and was associated with increased ligand-receptor interactions involving malignant cells via CD44 and ITGB1. These interactions were primarily observed in peri-tumoral and intratumoral regions, indicating a role for SPP1+ macrophages in modulating the TME and contributing to CCRT resistance. Further analysis revealed that SPP1-mediated cell-cell interactions predominantly occurred between macrophages and malignant epithelial cells, highlighting their potential role in driving therapeutic resistance.

Our findings suggest that SPP1-expressing macrophages play a pivotal role in the development of CCRT resistance in hypopharyngeal SCC through specific interactions with malignant cells. The spatial distribution of these macrophages and their interaction with cancer cells suggest a mechanism by which the TME contributes to therapeutic failure. These insights could inform the development of novel targeted therapies aimed at overcoming CCRT resistance, ultimately improving patient outcomes.