Divergent Immune–Metabolic Profiles in Endometriosis and Ovarian Cancer: A Cross-Sectional Analysis

Background/Objectives: Endometriosis and high-grade serous ovarian cancer (HGS-OC) share common features within the peritoneal immune microenvironment, yet they exhibit divergent clinical outcomes. This study aimed to dissect the immune–metabolic landscape of the peritoneal cavity in patients with endometriosis and ovarian cancer by evaluating macrophage polarization, intracellular signaling pathways, and iron-driven oxidative stress. Methods: A prospective cohort study enrolled 40 patients with endometriosis, 198 with ascitic ovarian cancer (178 HGS-OC), and 200 controls with benign gynecological conditions. Peritoneal and peripheral blood samples were analyzed via flow cytometry for macrophage (M1/M2) polarization markers, mTOR/AKT expression, and glucose uptake. Inflammatory markers (IL-6, CRP), oxidative stress (ROS), and iron metabolism parameters (hepcidin, ferritin, transferrin, serum/free iron) were quantified. Results: HGS-OC displayed a predominance of M1-polarized tumor-associated macrophages (TAMs) (CD14⁺/CD80⁺/Glut1⁺) and a high M1/M2 ratio (2.5 vs. 0.8 and 0.9; p = 0.019), correlating positively with IL-6 (p = 0.015), ROS (p = 0.023), hepcidin (p = 0.038), and ferritin (p = 0.043). Conversely, endometriosis showed a dominant M2 profile (CD14⁺/CD163⁺), elevated intracellular mTOR and AKT expression in both TAMs and epithelial cells (p < 0.01), and significantly higher ascitic ROS and free iron levels (p = 0.047 and p < 0.0001, respectively). In endometriosis, the M1/M2 ratio correlated inversely with free iron (p = 0.041), while ROS levels were directly associated with iron overload (p = 0.0034). Conclusions: Endometriosis exhibits a distinct immune–metabolic phenotype characterized by M2 macrophage predominance and iron-induced oxidative stress, contrasting with the inflammatory, M1-rich profile of HGS-OC. These findings suggest that iron metabolism and macrophage plasticity contribute to disease persistence in endometriosis and may inform future immunomodulatory strategies.