JAK-STAT Pathway Heterogeneity Governs Immunotherapy Response in Breast Cancer
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Curated by eLife
eLife Assessment
This multi-omics study provides a comprehensive characterization of the context-dependent roles of the JAK-STAT pathway (JSP) across different cellular compartments within the breast cancer microenvironment. The authors present convincing evidence that high JSP activity paradoxically drives anti-tumor cytotoxicity in T cells but promotes malignancy and immunosuppression in tumor epithelial cells, leading to the fundamental discovery that broad JAK-STAT inhibition could be therapeutically counterproductive. Ultimately, the identification of the immune-related JSP score and the STAT4 axis as predictive biomarkers for anti-PD-1 immunotherapy response, particularly in triple-negative breast cancer, offers critical insights for precise patient stratification and targeted therapeutic interventions.
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Abstract
The JAK–STAT pathway (JSP) is a well-known oncogenic cascade; however, recent clinical trials have detected JSP upregulation in breast cancer following anti-PD1 immunotherapy. This paradoxical observation warrants further investigation into JSP’s intercellular heterogeneity, tumor dynamics, molecular mechanisms, and clinical implications for immunotherapy. JSP expression showed dynamic shifts during breast cancer progression, with higher levels in T cells and para-cancerous epithelial cells. In tumor cells, elevated JSP highly correlated with malignant phenotypes. JSP-high tumor cells overexpressed oncogenic pathways, while exhibiting increased immunosuppressive signaling via MIF-CD74 signaling axis. In T cells, higher JSP levels were associated with enhanced cytotoxic activity, improved differentiation, and reduced exhaustion, reflecting robust anti-tumor immunity. Analysis of immunotherapy datasets revealed that higher JSP levels were associated with improved responses towards PD-1 inhibitors, particularly in triple-negative breast cancer (TNBC) patients, with JSP serving as a predictive biomarker for immunotherapy sensitivity. As a key JSP component, STAT4 exerts dual roles in breast cancer: it drives tumorigenesis in malignant cells, sustains breast epithelial cell proliferation, and bolsters T cell anti-tumor functionality—while also acting as a highly accurate biomarker for predicting immunotherapy response. This indicates that JSP targeting demands a nuanced approach: broad inhibition may impair anti-tumor immunity, and optimized therapeutic strategies paired with precise biomarkers are critical to maximize JSP’s utility in breast cancer immunotherapy. Our findings highlight JSP’s functional heterogeneity in epithelial, tumor, and T cells, with high JSP activity correlating with enhanced immunotherapy efficacy in breast cancer.
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eLife Assessment
This multi-omics study provides a comprehensive characterization of the context-dependent roles of the JAK-STAT pathway (JSP) across different cellular compartments within the breast cancer microenvironment. The authors present convincing evidence that high JSP activity paradoxically drives anti-tumor cytotoxicity in T cells but promotes malignancy and immunosuppression in tumor epithelial cells, leading to the fundamental discovery that broad JAK-STAT inhibition could be therapeutically counterproductive. Ultimately, the identification of the immune-related JSP score and the STAT4 axis as predictive biomarkers for anti-PD-1 immunotherapy response, particularly in triple-negative breast cancer, offers critical insights for precise patient stratification and targeted therapeutic interventions.
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Reviewer #1 (Public review):
Summary:
In their manuscript, Zhou and colleagues present a detailed look at how the JSP functions differently in the various cells of a breast tumor. The authors have effectively shown that the JSP acts as a double-edged sword, as it helps T cells fight cancer but also allows tumor cells to grow and avoid ferroptosis. These findings are important because they identify a useful biomarker to predict how TNBC patients might respond to PD-1 inhibitors.
Strengths:
This work is important because it provides a clear explanation for the conflicting roles of the JSP in the tumor environment. The evidence is solid, as it combines data from thousands of patients with single-cell analysis and lab experiments to confirm the role of STAT4 in cancer progression and immunity.
Weaknesses:
However, there are areas for …
Reviewer #1 (Public review):
Summary:
In their manuscript, Zhou and colleagues present a detailed look at how the JSP functions differently in the various cells of a breast tumor. The authors have effectively shown that the JSP acts as a double-edged sword, as it helps T cells fight cancer but also allows tumor cells to grow and avoid ferroptosis. These findings are important because they identify a useful biomarker to predict how TNBC patients might respond to PD-1 inhibitors.
Strengths:
This work is important because it provides a clear explanation for the conflicting roles of the JSP in the tumor environment. The evidence is solid, as it combines data from thousands of patients with single-cell analysis and lab experiments to confirm the role of STAT4 in cancer progression and immunity.
Weaknesses:
However, there are areas for improvement in the scope of the review, the depth of analysis, and the potential for broader clinical implications. The authors are encouraged to address these issues to enhance the scientific and clinical impact of the study.
Major Issues:
(1) The authors demonstrate that STAT4 upregulates SLC47A1, but this is currently supported only by expression correlation and western blot data. To confirm a direct link, the authors are encouraged to perform ChIP-qPCR or luciferase reporter assays to show that STAT4 binds directly to the SLC47A1 promoter.
(2) The conclusion that the MIF-CD74 axis drives immunosuppression is based on computational inference. To support this, the authors could consider mining publicly available breast cancer spatial transcriptomics data to show the co-localization of MIF and CD74. Alternatively, performing simple dual-color immunofluorescence staining on a few clinical sections would effectively demonstrate the physical proximity of these cells.
(3) TNBC is highly heterogeneous and includes subtypes like mesenchymal and immunomodulatory groups. The authors should analyze whether the JSP score or STAT4 levels vary significantly between these subtypes, as this could further refine the selection of patients for JAK1 inhibitors.
(4) While the JSP score works well in the current datasets, the authors should consider validating its predictive accuracy in additional independent immunotherapy cohorts, such as the TONIC trial, to ensure the biomarker is robust across different treatment settings.
Minor Issue:
The manuscript mentions a U-shaped trajectory of JSP activity during tumor transition. A more detailed biological explanation of why the pathway activity initially drops and then rises would add depth to the discussion.
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Reviewer #2 (Public review):
Summary:
The JAK-STAT pathway (JSP) exhibits cell-type-specific functional heterogeneity in breast cancer. This study investigates the JSP in breast cancer and its response to anti-PD‑1 immunotherapy. JSP displays distinct cell‑type heterogeneity: it promotes malignant phenotypes and immunosuppression in tumor cells, while enhancing cytotoxicity and reducing exhaustion in T cells. Elevated JSP expression correlates with improved immunotherapy responses, especially in triple‑negative breast cancer. These findings highlight the paradoxical roles of JSP, indicating that broad inhibition may compromise anti‑tumor immunity.
Strengths:
The major strengths of this study include the comprehensive characterization of JSP heterogeneity across epithelial, tumor, and T cells in breast cancer. The identification of JSP …
Reviewer #2 (Public review):
Summary:
The JAK-STAT pathway (JSP) exhibits cell-type-specific functional heterogeneity in breast cancer. This study investigates the JSP in breast cancer and its response to anti-PD‑1 immunotherapy. JSP displays distinct cell‑type heterogeneity: it promotes malignant phenotypes and immunosuppression in tumor cells, while enhancing cytotoxicity and reducing exhaustion in T cells. Elevated JSP expression correlates with improved immunotherapy responses, especially in triple‑negative breast cancer. These findings highlight the paradoxical roles of JSP, indicating that broad inhibition may compromise anti‑tumor immunity.
Strengths:
The major strengths of this study include the comprehensive characterization of JSP heterogeneity across epithelial, tumor, and T cells in breast cancer. The identification of JSP and STAT4 as predictive biomarkers for immunotherapy response, particularly in triple‑negative breast cancer, provides clinically relevant insights for patient stratification.
Weaknesses:
The findings rely heavily on public dataset analyses.
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Reviewer #3 (Public review):
Summary:
This multi-omics study by Zhou et al elucidates the context-dependent roles of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway (JSP) across different cellular compartments in the breast cancer tumor microenvironment. While bulk JSP activity is associated with a favorable prognosis, single-cell analysis reveals a paradoxical landscape: high JSP in T cells drives anti-tumor cytotoxicity and reduces exhaustion, whereas high activity in tumor epithelial cells promotes malignancy and immunosuppression via the MIF-CD74 signaling axis. The JSP score (immune-related) serves as a robust predictive biomarker for response to anti-PD-1 immunotherapy, particularly in triple-negative breast cancer (TNBC). Furthermore, the study identifies the STAT4/SLC47A1 axis as a critical …
Reviewer #3 (Public review):
Summary:
This multi-omics study by Zhou et al elucidates the context-dependent roles of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway (JSP) across different cellular compartments in the breast cancer tumor microenvironment. While bulk JSP activity is associated with a favorable prognosis, single-cell analysis reveals a paradoxical landscape: high JSP in T cells drives anti-tumor cytotoxicity and reduces exhaustion, whereas high activity in tumor epithelial cells promotes malignancy and immunosuppression via the MIF-CD74 signaling axis. The JSP score (immune-related) serves as a robust predictive biomarker for response to anti-PD-1 immunotherapy, particularly in triple-negative breast cancer (TNBC). Furthermore, the study identifies the STAT4/SLC47A1 axis as a critical mechanism through which tumor cells resist ferroptosis, facilitating disease progression. These findings suggest that broad JAK-STAT inhibition may be counterproductive in cancer therapeutics; instead, therapeutic success depends on precise modulation and carefully timed interventions to preserve its T-cell-associated functions. This study may inspire future studies to explore specific factors that selectively modulate JAK-STAT activity in immune cells to achieve favorable therapeutic outcomes.
Strengths:
Significant therapeutic implications.
Weaknesses:
Limited molecular mechanisms.
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