Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway.
Level 5 - mechanism / opinion, no new human data
Narrative review of mechanism-based reasoning and preclinical studies with no new clinical data.
PubMed 40712694 · doi:10.1016/j.mce.2025.112617
What was done
This narrative review synthesizes preclinical and mechanistic literature on the cyclooxygenase-2 (COX-2) / prostaglandin E2 (PGE2) signaling axis in breast cancer, evaluating EP receptor blockade, PGE2-degrading enzymes, and combinations with immune checkpoint inhibitors.
What was found
The abstract reports no quantitative values or statistical data. The review reports that PGE2 promotes an immunosuppressive tumor microenvironment via EP1–EP4 receptors by recruiting tumor-associated macrophages, dendritic cells, cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells, while inhibiting cytotoxic T and natural killer cell activity. Dual EP2/EP4 inhibition and EP4 antagonists paired with anti-PD-1 or anti-CTLA-4 enhanced T-cell infiltration and anti-tumor responses in preclinical models. Non-selective or broad upstream COX-2 inhibitors like celecoxib failed to improve survival in trials and carry cardiovascular risks.
Why it matters
The paper summarizes rationale for pursuing selective downstream targets of the PGE2 pathway (such as EP2/EP4 antagonism or 15-PGDH enhancement) alongside checkpoint inhibitors rather than relying on broad COX-2 inhibition.
Limits
This is a narrative review presenting no primary human trial data, quantitative effect estimates, or systematic search methodology. Most highlighted therapeutic strategies are limited to preclinical models, and clinical translation remains unproven given prior trial failures with broad COX-2 inhibitors.
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