Breast cancer (BC) is the most common malignancy among women worldwide and is associated with significant metabolic reprogramming (Zheng et al., 2022, Zheng et al., 2024). A key component of this reprogramming is the metabolism of arachidonic acid (AA), an essential fatty acid that can be derived from dietary sources such as meat, fish, poultry, seafood, and animal organs (Li et al., 1998; Taber et al., 1998; Komprda et al., 2005; Abedi and Sahari, 2014), as well as synthesized by organs like the brain, muscles, and liver (Bosisio et al., 1976; Bergstroem et al., 1964; Rahman et al., 1997). AA plays a crucial role in the development and progression of various cancers (Patel et al., 2008; Borin et al., 2017; Schneider and Pozzi, 2011), including BC, where its upregulation has been linked to enhanced metastatic potential and offers promise as a novel therapeutic target in BC treatment (Borin et al., 2017). AA is metabolized via three major enzymatic pathways: cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYP) monooxygenases. The COX pathway, in particular, is responsible for the dioxygenation of AA to generate prostaglandin H2 (PGH2), a precursor for all prostaglandins. The COX-regulated AA metabolism plays a pivotal role in tumor progression by mediating processes such as angiogenesis (Yao et al., 2011), epithelial-mesenchymal transition (EMT) (Balamurugan et al., 2023), and immune escape (Hutchinson, 2015), all of which contribute to cancer aggressiveness. Among the COXs, COX-2 is particularly influential in driving these processes through its metabolite, prostaglandin E2 (PGE2) (Hashemi Goradel et al., 2019).

Oncogenic transformation of tumor cells results in the adaptation of a distinct metabolic phenotype, which significantly influences the tumor microenvironment (TME) (Vander Heiden and DeBerardinis, 2017). The TME is characterized by nutrient competition, hypoxia, acidic conditions, and the accumulation of metabolic byproducts, all of which contribute to the immunosuppressive or tolerogenic phenotypes of immune cells (Li et al., 2023). Notably, AA metabolism reprogramming plays a key role in shaping this immunosuppressive TME. In various cancers, AA reprogramming has been shown to drive the polarization of tumor-associated macrophages (TAMs) in lung cancer (Li et al., 2023) and regulatory T cells (Tregs) in colorectal cancer (Zhan et al., 2021). The TME is further remodeled by crosstalk between cancer cells and immune cells, which in turn regulates BC development, progression, and metastasis (Liu et al., 2024). Targeting AA metabolism has emerged as a promising strategy to convert tumors from an immunologically “cold” to a “hot” state, reversing immune recognition and response (Li et al., 2023).

This review will focus on the key processes regulated by COXs in BC progression, with a particular emphasis on the COX-2/PGE2 pathway. We will explore how this pathway contributes to tumorigenesis by inducing an immunosuppressive TME and examine the complex crosstalk between immune cells and cancer cells in shaping the BC microenvironment.