Single-cell Transcriptomics Uncovers the Tumor Microenvironment and Collagen-CD44 Axis in HIV Positive Cervical Squamous Cell Carcinoma.

INTRODUCTION

Human immunodeficiency virus (HIV) infection markedly increases the incidence and worsens clinical outcomes of cervical squamous cell carcinoma (CSCC). The single-cell landscape of the tumor microenvironment (TME) in HIV positive CSCC (HIV-CSCC) remains poorly defined, and its cellular and molecular differences from HIV negative CSCC are largely unclear.

METHODS

We performed single-cell RNA sequencing (scRNA-seq) on tumor tissues from three HIV-CSCC patients without preoperative chemoradiotherapy. Public scRNA-seq data of three HIV negative CSCC cases were integrated as controls. We systematically analyzed cellular composition, transcriptional profiles, metabolic characteristics and intercellular communication networks across groups.

RESULTS

Epithelial cells in HIV-CSCC exhibited aggravated malignant phenotypes and metabolic disorders. The C5 epithelial subcluster was strongly associated with poor patient survival. Tumor-infiltrating T cells displayed impaired cytotoxic function. Macrophages predominantly polarized into immunosuppressive M2-like phenotypes with attenuated phagocytosis and antigen presentation. Cancer-associated fibroblasts (CAFs) acted as the core regulatory hub in HIV-CSCC TME and mediated cell crosstalk mainly via the collagen-CD44 signaling axis. Upregulated CD44 was an independent prognostic factor for unfavorable survival in HIV positive patients.

CONCLUSIONS

HIV-CSCC is characterized by a highly immunosuppressive TME and extensive stromal remodeling driven by activated CAFs. The collagen-CD44 pathway plays a key role in tumor progression. Our findings reveal the molecular mechanism of HIV-CSCC and identify CD44 as a promising therapeutic target for this disease.