Human papillomavirus-related syntaxin 11 reprograms tumor-associated macrophages to induce breast cancer cell apoptosis via PI3K/AKT signaling.

BACKGROUND: Human papillomavirus (HPV) is closely associated with tumor progression and the tumor microenvironment (TME), but its role in breast cancer (BC), which can be affected by HPV, has not been reported. METHODS: Ten independent BC cohorts were included to generate two HPV-related gene-based signatures. The CIBERSORT and ESTIMATE algorithms were used to quantify the immune cell fraction and TME scores, and the correlations between HPV-related gene-based signatures and scores were analyzed. The expression patterns and clinical significance of STX11 were determined through bioinformatics analysis, and its effects on modulating tumor-associated macrophages (TAMs) were confirmed by real-time qPCR and Western blotting. The anticancer role of STX11 in macrophages and its underlying mechanisms were analyzed in vitro and in vivo. RESULTS: Two novel HPV-related gene-based signatures were established that can effectively predict the overall survival and disease-free survival of patients with BC. HPV-related gene-based signatures were significantly associated with the immune score and 19 types of immune cells in BC tissues. STX11 was downregulated in BC and was associated with favorable clinical prognosis, and it was expressed mainly in M1 TAMs. Mechanistically, STX11 promoted the M1 polarization of macrophages, and macrophages overexpressing STX11 can inhibit BC proliferation and migration by regulating the PI3K-AKT pathway. In orthotopic BC models, macrophages overexpressing STX11 significantly suppressed tumor growth. CONCLUSIONS: HPV-related risk signatures were constructed, which showed prognostic predictive ability for patients with BC. STX11 is associated with a favorable prognosis in patients with BC and facilitates M1 polarization, and macrophages overexpressing STX11 can inhibit BC malignancy by regulating the PI3K-AKT pathway, suggesting its role as a potential immunotherapeutic candidate.