Eur J Surg Oncol. 2026 Feb 4;52(4):111425. doi: 10.1016/j.ejso.2026.111425. Online ahead of print.
ABSTRACT
BACKGROUND: HPV-negative cervical cancer (3-8% of cases) presents distinct clinical challenges and poorer prognosis compared to HPV-positive disease. We aimed to conduct an exploratory study to characterize its unique tumor immune microenvironment (TIME) and molecular drivers to inform immunotherapy development.
METHODS: We analyzed 70 cervical cancer patients (50 HPV-positive/HPV-A, 20 HPV-negative/HPV-I) using targeted next-generation sequencing and multiplex immunofluorescence. Clinical features, mutational profiles, immune cell infiltrates, and prognostic factors were compared between groups. Strict FDR correction and effect size analysis (Cliff’s Delta) were applied to statistical comparisons.
RESULTS: HPV-I tumors showed significant association with gastric-type adenocarcinoma (p < 0.001) and higher CA125 levels (p = 0.011). Molecularly, HPV-I tumors were substantially enriched for TP53 mutations (46.2% vs 2.2%, OR = 0.030, p < 0.001), while PIK3CA mutations predominated in HPV-A tumors (41.3% vs 7.7%, OR = 7.78, p = 0.047), suggesting notable mutual exclusivity. Immunologically, HPV-A tumors showed substantially higher stromal M2 macrophage density (Cliff’s Delta = -0.51, Large Effect), while HPV-I tumors displayed significantly higher stromal immune cell ratios: M1/M2 (5.34 vs 0.87, p = 0.003), CD8+/M2 (13.65 vs 2.66, p = 0.004), and NK/M2 (8.43 vs 0.59, p = 0.012), revealing the paradox of favorable immune balance coexisting with immune exclusion. In HPV-I subgroup analysis, high CD8+/M2 ratio was associated with superior progression-free survival (16.7% vs 71.4% event rates, p = 0.014).
CONCLUSIONS: HPV-negative and HPV-positive cervical cancers represent distinct entities with unique molecular and immunological profiles. Our exploratory findings suggest that HPV-I tumors exhibit the paradox of favorable stromal immune cell ratios coexisting with immune-excluded phenotype, while HPV-A tumors show higher M2 macrophage infiltration. The prognostic significance of CD8+/M2 ratio in HPV-I patients may provide a valuable biomarker and suggest specific therapeutic strategies targeting immune exclusion and macrophage polarization based on HPV status.
PMID:41795431 | DOI:10.1016/j.ejso.2026.111425
