Frontiers in immunology · 2026
Metabolic reprogramming of cholesterol biosynthesis drives macrophage-mediated immune suppression in HPV-negative cervical adenocarcinoma.
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Zhang Jianing, Wei Wenjuan, Zhang Yajun, Wang Daqing
Аннотация
BACKGROUND: Cervical adenocarcinoma is an increasingly common and aggressive subtype of cervical cancer with marked biological heterogeneity. Accumulating evidence suggests that HPV-positive and HPV-negative adenocarcinomas exhibit distinct immune microenvironments, but the underlying mechanisms remain unclear.
METHODS: Publicly available single-cell RNA sequencing datasets of cervical adenocarcinoma and normal cervical tissues were systematically analyzed using integrated bioinformatic approaches, including cell clustering, copy number variation inference, metabolic pathway analysis, and cell-cell communication modeling. Key findings were validated through in vitro experiments using cervical cancer cell lines, macrophage polarization assays, metabolic measurements, ELISA, immunofluorescence, and CD8+ T cell functional analyses.
RESULTS: Single-cell analysis revealed profound differences in cellular composition and immune states between HPV-negative and HPV-positive adenocarcinomas. HPV-negative tumors exhibited increased immune infiltration but were enriched for exhausted CD8+ T cells and immunosuppressive SPP1+ macrophages. Malignant epithelial cells from HPV-negative adenocarcinoma displayed distinct metabolic reprogramming characterized by activation of cholesterol biosynthesis pathways, elevated DHCR7 expression, and accumulation of the oxysterol 27-hydroxycholesterol (27-HC). Functionally, 27-HC induced macrophage polarization toward an immunosuppressive phenotype and promoted SPP1 secretion. Macrophage-derived SPP1, in turn, enhanced DHCR7 expression and 27-HC production in tumor cells via CD44, forming a positive feedback loop that reinforced immune suppression. Disruption of DHCR7 attenuated macrophage-mediated immunosuppression and alleviated CD8+ T cell exhaustion.
CONCLUSIONS: This study identifies a DHCR7-27-HC-SPP1 metabolic-immune axis that drives immune escape in HPV-negative cervical adenocarcinoma, highlighting cholesterol metabolism as a potential therapeutic vulnerability.
METHODS: Publicly available single-cell RNA sequencing datasets of cervical adenocarcinoma and normal cervical tissues were systematically analyzed using integrated bioinformatic approaches, including cell clustering, copy number variation inference, metabolic pathway analysis, and cell-cell communication modeling. Key findings were validated through in vitro experiments using cervical cancer cell lines, macrophage polarization assays, metabolic measurements, ELISA, immunofluorescence, and CD8+ T cell functional analyses.
RESULTS: Single-cell analysis revealed profound differences in cellular composition and immune states between HPV-negative and HPV-positive adenocarcinomas. HPV-negative tumors exhibited increased immune infiltration but were enriched for exhausted CD8+ T cells and immunosuppressive SPP1+ macrophages. Malignant epithelial cells from HPV-negative adenocarcinoma displayed distinct metabolic reprogramming characterized by activation of cholesterol biosynthesis pathways, elevated DHCR7 expression, and accumulation of the oxysterol 27-hydroxycholesterol (27-HC). Functionally, 27-HC induced macrophage polarization toward an immunosuppressive phenotype and promoted SPP1 secretion. Macrophage-derived SPP1, in turn, enhanced DHCR7 expression and 27-HC production in tumor cells via CD44, forming a positive feedback loop that reinforced immune suppression. Disruption of DHCR7 attenuated macrophage-mediated immunosuppression and alleviated CD8+ T cell exhaustion.
CONCLUSIONS: This study identifies a DHCR7-27-HC-SPP1 metabolic-immune axis that drives immune escape in HPV-negative cervical adenocarcinoma, highlighting cholesterol metabolism as a potential therapeutic vulnerability.