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Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway
Xuewei Zheng1, Junxiang Wang1, Yanan OuYang2
1Precision Medicine Laboratory, School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, 471003, China.
Abstract:
The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in breast cancer (BC) progression by promoting immune suppression, tumor growth, and metastasis. PGE2 mediates these effects through EP receptors (EP1-EP4), suppressing anti-tumor immunity while fostering an immunosuppressive tumor microenvironment (TME). This includes the recruitment and activation of tumor-associated macrophages (TAMs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), ultimately impairing cytotoxic T lymphocyte and natural killer (NK) cell function. Targeting the COX-2/PGE2 axis presents a promising strategy for BC treatment. Dual inhibition of EP2 and EP4 has demonstrated superior efficacy in reversing immune suppression compared to single-receptor blockade. Additionally, combining EP4 antagonists with immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 enhances T cell infiltration and tumoricidal activity, leading to improved therapeutic outcomes. Another emerging approach involves enhancing the activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for PGE2 degradation, to counteract PGE2-driven immune evasion. PTGES1 inhibitors have shown great potential in overcoming the immunosuppressive TME in BC patients. Elevated TIL levels in TNBC and HER2-positive BC are associated with improved prognosis; however, COX-2 inhibitors such as celecoxib failed to enhance survival and carry potential cardiovascular risks, highlighting the need for TIL-stratified trials to refine immunotherapeutic strategies. This review highlights the immunosuppressive mechanisms of the COX-2/PGE2 pathway in BC and explores novel therapeutic strategies targeting this axis. Understanding the intricate crosstalk between PGE2 signaling and immune modulation may lead to the development of more effective BC treatments, particularly in combination with immunotherapies.
Insights
The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway fuels breast cancer progression and immune suppression. Targeting this axis, especially with dual EP2/EP4 inhibition or combined therapies, offers promising strategies to enhance anti-tumor immunity and improve treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway is integral to breast cancer (BC) progression, driving immune suppression, tumor growth, and metastasis.
- PGE2 exerts its effects via EP receptors (EP1-EP4), fostering an immunosuppressive tumor microenvironment (TME) by recruiting immune-suppressing cells and impairing anti-tumor immune cell function.
Purpose of the Study:
- To review the immunosuppressive mechanisms of the COX-2/PGE2 pathway in breast cancer.
- To explore novel therapeutic strategies targeting this axis for improved BC treatment, particularly in combination with immunotherapies.
Main Methods:
- Literature review of studies investigating the COX-2/PGE2 pathway in breast cancer.
- Analysis of therapeutic strategies including EP receptor antagonism, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enhancement, and combination therapies with immune checkpoint inhibitors (ICIs).
Main Results:
- Dual inhibition of EP2 and EP4 receptors shows superior efficacy in reversing immune suppression compared to single blockade.
- Combining EP4 antagonists with ICIs (anti-PD-1, anti-CTLA-4) enhances T cell infiltration and anti-tumor activity.
- Enhancing 15-PGDH activity or inhibiting PTGES1 can counteract PGE2-driven immune evasion and overcome TME suppression.
Conclusions:
- Targeting the COX-2/PGE2 axis is a promising strategy for breast cancer treatment.
- Combination therapies, particularly with immune checkpoint inhibitors, hold significant potential for enhancing therapeutic outcomes.
- Further research, including TIL-stratified trials, is needed to optimize immunotherapeutic strategies targeting the COX-2/PGE2 pathway in BC.
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