Oluwatoyin Banjo

Background: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and its incidence continues to rise due to increasing rates of obesity and metabolic dysfunction.^{1, 2} Type I EC, the predominant subtype, is associated with prolonged estrogen exposure and dysregulated signaling pathways, which promote endometrial proliferation and carcinogenesis.² While EC has historically been characterized through hormonal and genetic mechanisms, emerging evidence suggests that interactions within the tumor microenvironment (TME) contribute significantly to disease progression.⁴ The TME consists of stromal cells, immune cells, inflammatory mediators, and metabolic products that collectively influence tumor behavior.⁴ Tumor-associated macrophages (TAMs), particularly M2-polarized macrophages, have gained attention due to their association with immunosuppression, angiogenesis, invasion, and metastatic progression.¹ Despite recognition of TAM involvement in EC, the mechanisms through which macrophage-mediated chemokine signaling and metabolic alterations sustain tumor progression remain incompletely understood.

Objective: This review explores the role of M2 macrophage polarization, CXCL1/CXCR2 signaling, and downstream NF-κB pathway activation as contributors to endometrial cancer progression and examines how metabolic and inflammatory alterations within the TME may inform future therapeutic development.

Search Methods: An online literature search of the PubMed database was conducted using the following keywords: “endometrial cancer,” “tumor-associated macrophages,” “CXCL1,” “CXCR2,” “NF-κB,” and “tumor microenvironment.” Articles published from 2018 to present were prioritized.

Results: Current literature demonstrates that M2 TAM infiltration is significantly elevated in EC and correlates with increased activation of inflammatory signaling pathways.⁵ Increased CD163 and CD206 expression has been observed in hyperplastic and malignant endometrial tissue, supporting enrichment of M2 macrophages within the TME.⁵ In EC, M2 TAMs have been identified as a major source of CXCL1, which binds CXCR2 receptors on tumor cells and activates NF-κB signaling, promoting proliferation, migration, epithelial–mesenchymal transition, and tumor progression.⁵ Additional studies indicate that metabolic reprogramming and increased aerobic glycolysis generate lactate, which promotes further M2 macrophage polarization and sustains a pro-tumor immune state.^3,6,7 Evidence from related gynecologic and solid tumor models suggests that inflammatory mediators, including IL-1β and IL7R signaling, reinforce CXCL1 expression through feed-forward activation of NF-κB signaling, creating a self-sustaining inflammatory feedback loop.^8,9 Early clinical investigation targeting CXCR2 signaling demonstrated the potential to alter immune cell infiltration and remodel the TME.¹⁰

Conclusions: Endometrial carcinogenesis extends beyond malignant epithelial transformation and involves dynamic interactions among metabolic, immune, and inflammatory components of the TME. M2 macrophage polarization and activation of the CXCL1/CXCR2–NF-κB signaling axis appear to contribute significantly to tumor progression and represent potential targets for future therapeutic intervention. Given the role of inflammatory signaling and immune cell recruitment in EC progression, targeting CXCR2 may have greater utility in limiting tumor progression and metastatic potential rather than inducing direct tumor regression. Continued investigation into modulation of chemokine signaling and tumor metabolism may improve treatment approaches and support more individualized therapies for patients with EC. In addition, further research is needed to determine whether CXCR2 inhibitors used in combination with current EC immunotherapies demonstrate therapeutic benefit.

Works Cited:

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9. Zhao H, Wei S, Zhou D, et al. Blocking the CXCL1-CXCR2 axis enhances the effects of doxorubicin in HCC by remodelling the tumour microenvironment via the NF-κB/IL-1β/CXCL1 signalling pathway. Cell Death Discov. 2023;9:120. doi:10.1038/s41420-023-01424-y
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