Beyond Iron: The Roles of CD71 in the Pathophysiology of Cancer—A Comprehensive Review

Abstract

CD71, also known as transferrin receptor 1 (TfR1), is a transmembrane glycoprotein essential for cellular iron uptake, a prerequisite for cell proliferation, differentiation, and survival. While its canonical role in iron metabolism is well documented, accumulating research highlights CD71’s broader involvement in oncogenic processes that extend far beyond iron regulation. This review provides an overview of recent advances in understanding the multifaceted roles of CD71 within cancer biology. Specifically, we examine how CD71 participates in key cancer-related mechanisms, including modulation of intracellular signaling cascades, such as MAPK/ERK and PI3K/AKT pathways. We also mention the impact on regulation of apoptosis and autophagy, and orchestration of dynamic interactions within the tumor microenvironment such as adhesion/invasion and immune evasion. Emerging evidence indicates that CD71 not only sustains tumor growth and cancer cell proliferation through enhanced iron acquisition but also promotes metastasis, immune evasion, and therapy resistance. Moreover, CD71 contributes to the crosstalk between cancer and chronic diseases, with notable implications for cardiac, neurological, and gastrointestinal conditions often linked to malignancy. Through a comprehensive synthesis of current findings, we elucidate the complex and evolving roles of CD71 in cancer progression and therapy and provide an up-to-date account of its biology and pathophysiology. This review underscores the importance of understanding CD71 not only in oncology but also across the broader field of chronic diseases associated with malignancy. We suggest that future work should advance innovative therapeutic approaches that leverage CD71’s dual roles in cancer biology and systemic disease management to improve patient outcomes.