Anshara Danish

Background: Endometrial cancer (EC) is one of the most common gynecologic malignancies in the United States. Type I EC, the predominant subtype, is hormone-driven and develops through a stepwise progression from benign endometrium through endometrial intraepithelial neoplasia (EIN) to invasive carcinoma.¹ Unopposed estrogen drives endometrial proliferation, while progesterone provides a counterbalancing differentiation signal. At the EIN stage, progestin therapy is the standard of care, but a substantial subset of patients does not respond.¹ This treatment failure highlights the need to understand how immune cells and pro-inflammatory cytokines shape hormonal signaling.⁴ Macrophages, in particular, are emerging as key modulators of hormone therapy responsiveness, motivating a closer look at how they interact with progesterone signaling during early EC progression.¹

Search Methods: An online search in the PubMed database was conducted from 2017-2025 using the following keywords: “endometrial cancer,” “macrophage infiltration,” “tumor-associated macrophages,” “progesterone receptor,” “progestin resistance,” “cytokine signaling,” “RNA sequencing,” and “tumor microenvironment.”

Results: Multiple studies demonstrated that there was increased macrophage infiltration in early endometrial cancer. Wang et al. reported almost a two-fold increase in CD163+ macrophages in progestin non-responders compared with responders along with a significant decrease in progesterone receptor expression.¹ RNA sequencing showed downregulation of progesterone responsive genes and upregulation of inflammatory and extracellular matrix pathways. ATAC sequencing displayed reduced chromatin accessibility at progesterone regulated regions. Additional mechanistic studies showed that macrophages secreted cytokines such as IL-10, TGF-β, and CCL18, which collectively promote invasion and dysregulate tumor signaling.¹˒² Notably, macrophage ERα-driven CCL18 secretion activated mTOR/KIF5B signaling in tumor cells and drove epithelial-to-mesenchymal transition.² Furthermore, CSF-1/CSF-1R signaling was shown to recruit macrophages into the tumor microenvironment, reinforcing pro-tumor immune signaling.³ Clinical studies demonstrated that patients who relapsed following initial progestin response displayed distinct immune exhaustion signatures and altered immune signaling patterns.⁵

Conclusion: Current evidence suggests that macrophages are active regulators of early endometrial cancer and progestin resistance. Through cytokine signaling, transcriptional reprogramming, and epigenetic modification, macrophages cause disturbances in progesterone signaling and promote tumor progression.¹⁻⁴ These findings suggest that immune-related biomarkers, such as macrophage infiltration and immune gene signatures, can potentially help in predicting treatment response and relapse risk.⁵ Future studies would be needed to validate these biomarkers and evaluate combined hormonal and immune targeted therapeutic strategies.

Works Cited:

1. Wang L, Lv Q, Wu P, et al. RNA-seq and ATAC-seq analysis of CD163(+) macrophage-induced progestin-insensitive endometrial cancer cells. Cancer Med. 2023;12(5):5964-5978. doi:10.1002/cam4.5396
2. Jing X, Peng J, Dou Y, et al. Macrophage ERα promoted invasion of endometrial cancer cell by mTOR/KIF5B-mediated epithelial to mesenchymal transition. Immunol Cell Biol. 2019;97(6):563-576. doi:10.1111/imcb.12245
3. Hua F, Tian Y, Gao Y. Colony-stimulating factor 1 receptor inhibition blocks macrophage infiltration and endometrial cancer cell proliferation. Mol Med Rep. 2019;19(4):3139-3147. doi:10.3892/mmr.2019.9963
4. Gu X, Shi Y, Dong M, et al. Exosomal transfer of tumor-associated macrophage-derived hsa_circ_0001610 reduces radiosensitivity in endometrial cancer. Cell Death Dis. 2021;12:818. doi:10.1038/s41419-021-04087-8
5. Bowen MB, Melendez B, Zhang Q, et al. Long-term follow-up of levonorgestrel intrauterine device for atypical hyperplasia and early endometrial cancer reveals relapse characterized by immune exhaustion. Clin Cancer Res. 2024;30(22):5073-5082. doi:10.1158/1078-0432.CCR-24-0362