ORIGINAL RESEARCH article
Front. Oncol.
Sec. Molecular and Cellular Oncology
Molecular Remodeling of Cancer-Associated Fibroblasts in Breast Cancer Patients Receiving Anti–PD-1 Immunotherapy
Provisionally accepted
- Phenikaa University, Hanoi, Vietnam
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Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment that modulate the response to immune checkpoint inhibitors, particularly in breast cancer. However, the specific roles of CAF subtypes in regulating the efficacy of anti-PD-1 therapy remain poorly elucidated. In this study, we reanalyzed single-cell RNA sequencing data from breast cancer patients treated with anti-PD-1 inhibitors to identify CAF subtypes and characterize their molecular signatures. Four distinct CAF subtypes were identified: vascular CAFs (vCAF), myofibroblastic CAFs (myCAF), inflammatory CAFs (iCAF), and antigen-presenting CAF-like (apCAF-like) cells. Spatial transcriptomics mapping revealed that these subtypes occupy distinct anatomical niches, with myCAFs localized to fibrotic stromal regions and iCAFs found within immune-rich, inflamed areas. Our results demonstrate that clinical response to anti-PD-1 therapy is associated with divergent stromal interaction trajectories. In responders, stromal remodeling occurs, characterized by the functional re-education of iCAFs and the concurrent disarmament of vCAF and myCAF populations. Notably, iCAFs transition to a pro-inflammatory CXCL9-CXCR3 axis during treatment, facilitating immune recruitment and enhancing T-cell infiltration. This shift is accompanied by the attenuation of tumor-protective signals, which otherwise safeguard malignant cells. In contrast, resistance in non-responders is linked to stromal fortification, where CAFs sustain protective networks around the tumor niche. Therapeutic resistance is marked by a broad-spectrum suppressive response, driven by the apCAF-like-derived THBS2-CD47 axis and the pathological intensification of the vCAF-derived CXCL12-CXCR4 axis. These pathways are associated with dysfunctional lymphoid sequestration and the recruitment of immunosuppressive cell populations, such as plasmacytoid dendritic cells. Collectively, these findings highlight the critical role of CAF heterogeneity and spatial organization in modulating the response to anti-PD-1 therapy. Targeting subtype-specific stromal modules may represent a promising therapeutic strategy to enhance the efficacy of immunotherapy in breast cancer.
Keywords: Anti-PD-1 Therapy, breast cancer, CAF subtypes, Cancer-associated fibroblasts (CAF), immune checkpoint inhibitors, Immune Resistance, single-cell RNA sequencing, Tumor Microenvironment
Received: 25 Nov 2025; Accepted: 30 Jan 2026.
Copyright: © 2026 DO, Tran, Pham, Mac, PHAM and Do. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: KHANH VAN DO
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