The solute carrier family 11 transporters: a bridge between iron homeostasis and tumor biology

Abstract

Iron is an essential trace element in the human body, and its imbalance is closely linked to the initiation and progression of various malignancies. The solute carrier family 11 (SLC11) transporters, comprising SLC11A1 and SLC11A2, play pivotal roles in iron metabolism and cellular homeostasis, processes intricately linked to oncogenesis. SLC11A1, primarily expressed in macrophages, modulates immune responses and reshapes the tumor microenvironment, while SLC11A2, a ubiquitous iron transporter, regulates dietary iron absorption and ferroptosis, an iron-dependent form of programmed cell death. Dysregulation of these transporters is associated with tumor initiation, progression, metastasis, and therapy resistance. In this review, we provide an overview of the physiological functions of SLC11 transporters in iron metabolism and their pathological roles in cancer biology. Emerging evidence highlights their involvement in key oncogenic pathways, including p53, JAK/STAT, Wnt and HIF signaling. Pharmacological and genetic interventions targeting SLC11 transporters have shown the potential to disrupt tumor progression and enhance treatment efficacy. By exploring the intricate roles of SLC11A1 and SLC11A2 in cancer progression, this review offers insights into their potential as biomarkers and therapeutic targets, paving the way for innovative cancer treatment strategies.

Keywords: Cancer; Iron; Iron transporters; SLC11A1; SLC11A2.

Fig. 1

Schematic representation of secondary structure of a SLC11A1 and b SLC11A2. Mutations in SLC11A1 are marked in red, while specific motifs and substitutions are color-coded for clarity—light pink: YGSI motif; dark pink: alanine substitutions at positions occupied by tyrosine and isoleucine; violet: transport motif involved in ion transport and protein functionality. For SLC11A2, blue color indicates locations of known human mutations resulting in microcytic anemia; beige color: DPGN motif; violet: residues directly involved in the transport mechanism of SLC11A2; and green color: consensus transport signature

Fig. 2

Role of SLC11A1 in cancer. Expression patterns: SLC11A1 shows differential expression across various cancer types. Genetic variations: Key polymorphisms and mutations associated with cancer susceptibility and progression. Molecular pathways: SLC11A1 regulates immune modulation, inflammation, and tumor microenvironment remodeling. Therapeutic implications: SLC11A1 influences response to chemotherapy and immunotherapy and is associated with isocitrate dehydrogenase (IDH) mutations and survival outcomes. Green: upregulated, red: downregulated

Fig. 3

Role of SLC11A2 in cancer. Expression patterns of SLC11A2 in various cancers: Upregulated (green), downregulated (red), and differentially expressed (yellow). SLC11A2 modulates cancer cell fate by influencing iron metabolism, ferroptosis, mitophagy, and key signaling pathways such as IL-6/PI3K/AKT and STAT3. Therapeutic implications of SLC11A2 include its impact on chemotherapeutic sensitivity, cancer cell proliferation, and clinical outcomes

Fig. 4

Upregulated SLC11A1 activates JAK/STAT3 signaling, increasing the expression of immunosuppressive factors (CCL2 and PD-L1), which can be blocked by the JAK inhibitor AG490. These factors promote epithelial-to-mesenchymal transition, enhancing cancer cell proliferation, migration, and invasion, while also driving immunosuppression by promoting M2 macrophages and inducing CD8⁺ T cell apoptosis

Fig. 5

The impact of SLC11A2 silencing via siRNA or pharmacological intervention on oncogenic signaling and tumor progression. Silencing SLC11A2 disrupts key pathways, including p53-mediated cell cycle arrest, hypoxia signaling, Notch signaling, PI3K/AKT/mTOR signaling, and STAT3 activation. This leads to reduced cell growth, survival, angiogenesis, and metastasis, highlighting SLC11A2 as a potential therapeutic target in cancer

Fig. 6

Ferroptosis induction through SLC11A2/DMT1 upregulation and iron-dependent ROS accumulation. Various compounds, including HO-3867, temozolomide, sulfasalazine, heteronemin, and benja-ummarit, regulate DMT1, leading to increased Fe²⁺ uptake. Elevated Fe²⁺ triggers the Fenton reaction, producing ROS, which drive lipid peroxidation and ferroptosis. Additionally, ferritinophagy releases Fe²⁺ through NCOA4-mediated ferritin degradation, further amplifying oxidative stress. Biomarkers of ferroptosis include MDA, CD48 and GPX4