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JAK/STAT-mediated regulation of PD-L1 expression in breast cancer: Molecular mechanisms and implications for
1Pharmacy Department, Zhongshan Hospital Wusong Branch, Fudan University (Shanghai Baoshan District Wusong Central Hospital), Baoshan, Shanghai 200940, China.
Abstract:
Immune checkpoint blockade targeting the PD-1/PD-L1 axis has expanded treatment options for breast cancer, particularly triple-negative disease, yet therapeutic responses are limited by immune escape mechanisms. This review synthesizes mechanistic evidence showing how JAK/STAT signaling, predominantly through STAT1 and STAT3, integrates inflammatory cues, oncogenic stress, and microenvironmental signals to regulate PD-L1 expression across tumor cells and immune compartments. Experimental studies using cell lines, patient specimens, and in vivo models reveal that cytokines, hypoxia, metabolic remodeling, and extracellular vesicles sustain STAT-dependent PD-L1 programs that dampen cytotoxic immunity and promote resistance to therapy. The review further examines pharmacologic, genetic, and nanotechnology-based strategies that disrupt this signaling axis and enhance immune checkpoint efficacy, including combination regimens with chemotherapy, targeted therapy, and photodynamic approaches. Collectively, these findings position JAK/STAT-driven PD-L1 regulation as a unifying framework for understanding immune evasion and optimizing immunotherapy in breast cancer.
Insights
Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling drives programmed death-ligand 1 (PD-L1) expression in breast cancer, leading to immune escape. Targeting this pathway can enhance immunotherapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway offer new treatment avenues for breast cancer, especially triple-negative breast cancer.
- Therapeutic efficacy is often constrained by immune escape mechanisms inherent to the tumor microenvironment.
Purpose of the Study:
- To review the mechanistic evidence linking Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling to programmed death-ligand 1 (PD-L1) expression in breast cancer.
- To explore strategies for disrupting JAK/STAT-mediated PD-L1 regulation to improve immunotherapy outcomes.
Main Methods:
- Synthesis of mechanistic evidence from cell lines, patient specimens, and in vivo models.
- Review of experimental studies investigating the role of cytokines, hypoxia, metabolic changes, and extracellular vesicles in regulating STAT-dependent PD-L1.
- Examination of therapeutic strategies targeting the JAK/STAT axis.
Main Results:
- JAK/STAT signaling, particularly via STAT1 and STAT3, integrates various signals to control PD-L1 expression in both tumor and immune cells.
- STAT-dependent PD-L1 programs, sustained by factors like cytokines and hypoxia, suppress anti-tumor immunity and contribute to therapeutic resistance.
- Pharmacologic, genetic, and nanotechnological interventions targeting JAK/STAT signaling show promise in enhancing immune checkpoint therapy.
Conclusions:
- JAK/STAT-driven PD-L1 regulation represents a critical mechanism of immune evasion in breast cancer.
- Disrupting this signaling axis offers a promising framework for optimizing immunotherapy and overcoming resistance in breast cancer treatment.
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