This study utilizes single-cell RNA sequencing and spatial transcriptomic technologies to identify a novel cervical cancer-associated fibroblast (CD54⁺ iCAFs) interaction mechanism with ITGAL⁺ macrophages, revealing their immune escape promotion through the CXCL8-PD-L1 axis and providing new combination strategies for cervical cancer immunotherapy.
Literature Overview
The article 'Integrated multi-omics identifies a CD54+ iCAF-ITGAL+ macrophage niche driving immunosuppression via CXCL8-PDL1 axis in cervical cancer', published in 'Molecular Cancer', reviews the interaction mechanisms between fibroblasts and macrophages in cervical cancer tumor microenvironment. Through multi-omics integrated analysis, the study identifies CD54⁺ iCAFs co-localizing with ITGAL⁺ macrophages at the tumor-stromal interface, forming an immunosuppressive microenvironment via dual mechanisms of CCL2 secretion and CD54–ITGAL contact-dependent signaling. These mechanisms promote macrophage polarization toward M2-like phenotypes and activate the CXCL8-PD-L1 signaling axis to suppress CD8+ T cell function, providing theoretical basis for immune checkpoint therapy resistance.
Background Knowledge
Cervical cancer ranks as the fourth most common malignancy in women globally. Advanced and recurrent cases face limited treatment options with low response rates to immune checkpoint blockade therapies, suggesting strong immunosuppressive mechanisms exist in the tumor microenvironment. Cancer-associated fibroblasts (CAFs) and monocytic phagocytes (MPs) interact within tumor microenvironments to form immune-privileged niches, though specific mechanisms in cervical cancer remain unclear. This study systematically deciphers the bidirectional signaling network between CD54⁺ iCAFs and ITGAL⁺ macrophages using scRNA-seq and spatial multi-omics technologies, demonstrating their critical roles in immune escape and validating the CXCL8–CXCR1/2 pathway as a potential therapeutic target. Additionally, the study evaluates the therapeutic potential of Reparixin combined with PD-L1 blockade, providing experimental evidence for developing novel combination therapies.
Research Methods and Experiments
The research team performed single-cell RNA sequencing on six cervical cancer and four normal cervical tissue samples, obtaining 77,221 high-quality cells. Ligand-receptor interaction network analysis revealed specific signaling crosstalk between CD54⁺ iCAFs and ITGAL⁺ macrophages. Multiplex immunohistochemistry (mIHC) and spatial transcriptomics confirmed co-localization of CD54⁺ iCAFs and ITGAL⁺ macrophages at the tumor-stromal interface. Western blot, ELISA, Transwell migration assays, and loss/gain-of-function experiments analyzed CD54 and CCL2 expression-secretion dynamics in fibroblasts. The study further assessed Reparixin (CXCL8–CXCR1/2 inhibitor) effects on PD-L1⁺ macrophage populations and CD8+ T cell cytotoxic function.
Key Conclusions and Perspectives
Research Significance and Prospects
This study represents the first demonstration of CD54⁺ iCAF–ITGAL⁺ macrophage immunosuppressive microenvironment formation in cervical cancer and proposes targeting the CXCL8–CXCR1/2 pathway as a combination therapy strategy. Future research should evaluate the conservation of this signaling axis across other squamous epithelial cancers, explore its application value in predicting immune therapy resistance, and develop more precise targeted intervention approaches.
Conclusion
By integrating single-cell transcriptomics with spatial multi-omics technologies, this study systematically elucidates the interaction mechanisms between CD54⁺ iCAFs and ITGAL⁺ macrophages in cervical cancer microenvironments. CD54⁺ iCAFs employ dual pathways - CCL2 secretion and CD54–ITGAL receptor contact - to induce macrophage polarization toward M2-like phenotypes, subsequently activating the CXCL8–PD-L1 signaling axis that suppresses CD8+ T cell function and establishes immune tolerance. Therapeutic intervention with Reparixin effectively restores T cell activity, with PD-L1 blockade demonstrating synergistic antitumor effects. This research provides new theoretical foundations for understanding cervical cancer immunotherapy resistance mechanisms, suggesting that targeting the CD54⁺ iCAF–ITGAL⁺ macrophage axis may represent a potential strategy to reverse immunosuppression.
