HPV Infection Drives CXCL8+ Neutrophil-Mediated Immune Suppression in Cervical Cancer

Abstract

Persistent HPV infection is a major risk factor for cervical cancer, but the immune mechanisms behind HPV-induced tumor progression are not fully understood. Neutrophils may play a key role in immune remodeling and evasion within the HPV-infected tumor microenvironment. We integrated 31 cervical samples (including HPV-infected and non-infected normal, tumor, and HSIL tissues) to construct a single-cell atlas of 141,785 cells. Neutrophil heterogeneity, cell–cell communication, and immunosuppressive programs were systematically analyzed. Transcriptomic findings were validated via immunohistochemistry, immunofluorescence, and Mendelian randomization (MR). HPV infection dramatically remodeled the immune landscape, inducing robust neutrophil and plasma cell infiltration while reducing T cell abundance. Neutrophils in HPV+ tissues were terminally differentiated and displayed a distinct CXCL8⁺ phenotype. These CXCL8⁺ neutrophils were identified as late-stage, transcriptionally defined low-plasticity state enriched with immunosuppressive genes (e.g., SPP1, VEGFA). They exhibited enhanced interactions with T cell subsets, particularly regulatory and cytotoxic T cells, via ligands like CXCL16 and APOE, suggesting direct immunosuppressive crosstalk. MR analysis indicated a causal role for CXCL8 in cervical cancer, and spatial protein assays confirmed elevated CXCL8 and its receptor CSF3R in HPV+ tumors. HPV infection expands immunosuppressive CXCL8⁺ neutrophils that modulate T cell activity and promote immune escape. CXCL8 is identified as a causal factor and potential therapeutic target in HPV-driven cervical cancer.