Deconstructing cervical cancer heterogeneity: squamous cell carcinoma subtypes and CCM2 vulnerability in adenocarcinoma

Cervical cancer, a leading female malignancy with marked histological heterogeneity, encompassing squamous cell carcinoma (SCC), adenocarcinoma (AC), adenosquamous carcinoma (ASC), and neuroendocrine carcinoma (NEC), which differ in prognosis and treatment response. However, the molecular features of these histotypes, particularly the rare ASC and NEC subtypes, remain incompletely understood, and a dedicated molecular classification for SCC is lacking, limiting the development of subtype-specific therapeutic strategies. We performed deep proteomic profiling of 404 cervical cancer tissue samples, comprising 298 SCC, 74 AC, 22 ASC, and 10 NEC cases. Comparative proteomic, pathway enrichment, tumor microenvironment, survival, and machine-learning analyses were conducted to characterize subtype-specific molecular features, identify candidate therapeutic targets, and develop a prognostically relevant molecular classification system for SCC. Distinct proteomic signatures were observed between SCC and AC. AC was characterized by activation of epithelial-mesenchymal transition and glycoprotein metabolic pathways, and CCM2 was functionally validated as a candidate mediator of AC cell invasion and migration. SCC was classified into three cervical squamous molecular subtypes (CSMSs): CSMS1 (immunosuppressive), CSMS2 (immune-enriched), and CSMS3 (oxidative stress response). This classification significantly stratified patient survival in an independent external cohort (log-rank p = 0.022). Clinical-molecular subtype analysis showed the CSMS1 subtype had the poorest prognosis in specific subgroups (age > 45, BMI < 25 kg/m 2 , moderate differentiation, FIGO III/IV), especially with non-surgical treatment, supporting “clinical + molecular” stratification for high-risk identification. This large-scale proteomic study provides a comprehensive molecular landscape of the major histotypes of cervical cancer, identifies CCM2 as a potential therapeutic target associated with the aggressive phenotype of AC, and establishes a clinically relevant molecular classification system for SCC. Integrating the CSMS classification with conventional clinical characteristics may improve the identification of high-risk patients and facilitate precision management of cervical cancer.