HPV viral load predicts immune exhaustion and prognosis in cervical neoplasia

Persistent infection with high-risk human papillomavirus (HPV) is the primary cause of cervical cancer; however, the prognostic role of HPV viral load and its association with the tumor immune microenvironment remain incompletely understood. This study aimed to systematically evaluate the association between HPV viral load and disease progression, prognosis, and tumor immune microenvironment in patients with cervical cancer.

A retrospective cohort of 278 patients with cervical neoplasia was analyzed. HPV viral load was quantified and log₁₀-transformed. Patients were categorized into low- and high-viral load groups using segmented regression. Clinical characteristics, recurrence, metastasis, and survival were compared. Immune parameters (CD3⁺, CD4⁺, CD8⁺, FOXP3⁺ T cells, programmed death-ligand 1 [PD-L1] expression), serum tumor markers (squamous cell carcinoma antigen [SCC], cancer antigen 125 [CA125], CA199, carcinoembryonic antigen [CEA]), Ki67, p16, and sex hormone levels were assessed.

High HPV viral load (log₁₀ ≥5.6) was significantly associated with advanced disease stage (p < 0.001), lymph node metastasis (28.3% vs. 13.5%, p = 0.002), and higher recurrence rates (27.4% vs. 13.0%, p = 0.002). Five-year overall survival (OS) (68.5% vs. 87.3%) and recurrence-free survival (RFS) (59.3% vs. 82.1%) showed a trend toward worse outcomes in the high viral load group, but the differences were not statistically significant (log-rank p = 0.38 and p = 0.068, respectively). Multivariable Cox analysis confirmed high viral load as an independent predictor of recurrence (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.32-3.61, p = 0.002). High viral load correlated with reduced tumor-infiltrating lymphocytes (TILs) (CD3⁺: 12.1% vs. 18.3%, p = 0.001), lower PD-L1 positivity (36.4% vs. 63.2%, p = 0.045), and higher Ki67 expression (58.3% vs. 42.5%, p = 0.003). Combining viral load with serum SCC improved prediction of high-grade lesions (area under the curve [AUC] 0.78 vs. 0.73, p = 0.02) and recurrence (C-index 0.71 vs. 0.65). Machine learning models ranked viral load as the top predictor. Post-treatment viral load decline was significantly associated with lower recurrence risk (odds ratio [OR] 4.12 for slow decline, p = 0.02). In premenopausal women, estradiol levels correlated positively with viral load (ρ = 0.31, p = 0.003) and disease severity. A correlation network revealed a cluster linking high viral load, low immune infiltration, and high proliferation. The prognostic effect of viral load was consistent across HPV types and was more pronounced in advanced-stage patients (interaction p = 0.09).

High HPV viral load is an independent predictor of poor prognosis in cervical cancer, associated with an immunosuppressive tumor microenvironment and enhanced proliferative activity. Incorporating viral load into routine assessment may improve risk stratification and guide personalized treatment strategies, particularly for patients with high viral load who may benefit from immune-enhancing therapies.