The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment.

The solute carrier family 7 member 11 (SLC7A11), an amino acid transporter protein is frequently overexpressed in human malignancies. The expression and activity of SLC7A11 is finely regulated by oncogenes and tumor suppressors in tumor cells through various mechanisms and is highly specific for cystine and glutamate. Cystine is mainly transported intracellularly by SLC7A11 in the tumor microenvironment (TME) and is involved in GSH synthesis, which leads to ferroptosis resistance in tumor cells and promotes tumorigenesis and progression. The downregulation of SLC7A11 presents a unique drug discovery opportunity for ferroptosis-related diseases. Experimental work has shown that the combination of targeting SLC7A11 and tumor immunotherapy triggers ferroptosis more potently. Moreover, immunotargeting of SLC7A11 increases the chemosensitivity of cancer stem cells to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. Thus, SLC7A11 could be a promising target to overcome resistance mechanisms in conventional cancer treatments. This review provides an overview of the regulatory network of SLC7A11 in the TME and progress in the development of SLC7A11 inhibitors. In addition, we summarize the cytotoxic effects of blocking SLC7A11 in cancer cells, cancer stem cells and immune cells.

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