Iron metabolism in ovarian cancer: immune reprogramming, therapeutic resistance, and a hypothesis-driven translational roadmap for future trials
Year: 2026
Type: article
Abstract: Ovarian cancer remains a leading cause of gynecological cancer mortality. Late diagnosis, peritoneal dissemination, platinum resistance, ascites-driven relapse, and limited sensitivity to immune checkpoint inhibitors constrain durable treatment benefit. This review examines iron metabolism as a mechanistic bridge between clinical resistance and therapeutic selection. Throughout, we distinguish ovarian cancer-specific evidence from mechanistic hypotheses extrapolated from other tumor types and from proposals that remain unvalidated in patients. We first synthesize how iron acquisition, storage, export, heme metabolism, ferritin dynamics, and ferroptosis-defense pathways shape ovarian cancer biology. Particular attention is given to TFR1, ferroportin, STEAP3, ferritin, HMOX1, SLC7A11, GPX4, ACSL4, and lipid-remodeling programs. We then analyze iron-immunity crosstalk across tumor-associated macrophages, CD8+ T cells, myeloid-derived suppressor cells, regulatory T cells, dendritic cells, stromal cells, and ascites spheroids. Key mechanisms include HMOX1-linked macrophage remodeling, CD8+ T-cell-induced ferroptosis, tumor-intrinsic escape from immune-imposed lipid peroxidation, impaired antigen presentation, and ascites-mediated ferroptosis resistance. Finally, we outline biomarker-defined candidate combinations of iron modulation or ferroptosis sensitization with checkpoint blockade, platinum/PARP-based therapy, myeloid targeting, nanomedicine, and ascites-directed treatment. Iron metabolism constitutes a potentially actionable control layer connecting ovarian tumor survival, ferroptosis resistance, myeloid suppression, and T-cell failure. Clinical translation will require compartment-specific targeting, predictive biomarkers, context-preserving models, and protection of host hematologic and immune function.
Authors: Sufen Li, You Li, Xiaofei Sun, Rongkai Xie, Yake Huang
Institutions: Army Medical University, Xinqiao Hospital
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,890
OpenAlex ID: W7225748153
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