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<p>Single-cell sequencing has revolutionized our understanding of cervical cancer (CC), revealing unprecedented cellular heterogeneity, tumor microenvironment (TME) dynamics, and molecular mechanisms underlying progression and therapy resistance. These technologies have identified distinct molecular subtypes (hypoxic, proliferative, and immunoreactive) and epithelial states (cytokeratin⁺, immune-interacting, and senescent), while uncovering HPV-driven oncogenic mechanisms, including viral integration hotspots (e.g., 8q24.21) and immune evasion strategies (e.g., SPP1⁺ TAMs and GALNT3-mediated immunosuppression). Metabolic reprogramming further stratifies tumors into spatially organized Warburg effect and OXPHOS-dominant niches, each associated with unique immune infiltration patterns. The TME exhibits a complex interplay between exhausted PD-1⁺LAG3⁺TIM3⁺ T cells, immunosuppressive stromal cells (MYH9⁺ CAFs, PODXL⁺ ECs), and rare but potent effector populations (FGFBP2⁺ NK cells, CXCL13⁺ TRMs). Despite these advances, clinical translation faces challenges, including resistance mechanisms (NFKB1 mutations, BCL10⁺ Treg suppression) and a lack of inhibitors for key targets (PCLAF⁺ TAEpis, MYH9⁺ CAFs). Promising therapeutic strategies include epigenetic modulation (SALL4), sialylation inhibition (GALNT3/12), and immune-stromal co-targeting (PD-1 + LAG3/TIM3, NRG1-ERBB3 blockade). Future efforts must prioritize functional validation of novel targets (DKK2, ELF3), spatial multi-omics to resolve CAF-immune-metabolic crosstalk, and biomarker-driven clinical trials integrating single-cell classifiers. By bridging single-cell insights with mechanistic and translational studies, the field can overcome stromal-mediated resistance and usher in an era of precision immunotherapy for CC.</p> Graphical Abstract <p>This illustration captures how single-cell sequencing unveils cervical cancer’s complex landscape, revealing HPV-driven oncogenesis (viral integration at 8q24.21, GALNT3-mediated immune evasion), metabolic heterogeneity (Warburg/OXPHOS niches), and an immunosuppressive microenvironment (exhausted PD-1 + LAG3 + TIM3 + T cells, MYH9 + CAFs). Key resistance mechanisms (NFKB1 mutations, BCL10 + Treg suppression) and actionable targets (SALL4, NRG1-ERBB3) are highlighted, along with emerging strategies like immune-stromal co-targeting. The visual integrates multi-omics data with a translational pipeline, emphasizing challenges in overcoming stromal resistance and clinical implementation, while pointing toward precision immunotherapy solutions</p> <p></p>

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Advancements in single-cell sequencing for cervical cancer research

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月6日

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  • Congli Pu,
  • Biyuan Xing,
  • Shujie Wang,
  • Zhao Liu,
  • Yingchao Zhao

摘要

Single-cell sequencing has revolutionized our understanding of cervical cancer (CC), revealing unprecedented cellular heterogeneity, tumor microenvironment (TME) dynamics, and molecular mechanisms underlying progression and therapy resistance. These technologies have identified distinct molecular subtypes (hypoxic, proliferative, and immunoreactive) and epithelial states (cytokeratin⁺, immune-interacting, and senescent), while uncovering HPV-driven oncogenic mechanisms, including viral integration hotspots (e.g., 8q24.21) and immune evasion strategies (e.g., SPP1⁺ TAMs and GALNT3-mediated immunosuppression). Metabolic reprogramming further stratifies tumors into spatially organized Warburg effect and OXPHOS-dominant niches, each associated with unique immune infiltration patterns. The TME exhibits a complex interplay between exhausted PD-1⁺LAG3⁺TIM3⁺ T cells, immunosuppressive stromal cells (MYH9⁺ CAFs, PODXL⁺ ECs), and rare but potent effector populations (FGFBP2⁺ NK cells, CXCL13⁺ TRMs). Despite these advances, clinical translation faces challenges, including resistance mechanisms (NFKB1 mutations, BCL10⁺ Treg suppression) and a lack of inhibitors for key targets (PCLAF⁺ TAEpis, MYH9⁺ CAFs). Promising therapeutic strategies include epigenetic modulation (SALL4), sialylation inhibition (GALNT3/12), and immune-stromal co-targeting (PD-1 + LAG3/TIM3, NRG1-ERBB3 blockade). Future efforts must prioritize functional validation of novel targets (DKK2, ELF3), spatial multi-omics to resolve CAF-immune-metabolic crosstalk, and biomarker-driven clinical trials integrating single-cell classifiers. By bridging single-cell insights with mechanistic and translational studies, the field can overcome stromal-mediated resistance and usher in an era of precision immunotherapy for CC.

Graphical Abstract

This illustration captures how single-cell sequencing unveils cervical cancer’s complex landscape, revealing HPV-driven oncogenesis (viral integration at 8q24.21, GALNT3-mediated immune evasion), metabolic heterogeneity (Warburg/OXPHOS niches), and an immunosuppressive microenvironment (exhausted PD-1 + LAG3 + TIM3 + T cells, MYH9 + CAFs). Key resistance mechanisms (NFKB1 mutations, BCL10 + Treg suppression) and actionable targets (SALL4, NRG1-ERBB3) are highlighted, along with emerging strategies like immune-stromal co-targeting. The visual integrates multi-omics data with a translational pipeline, emphasizing challenges in overcoming stromal resistance and clinical implementation, while pointing toward precision immunotherapy solutions