Exploring the dual role of the cystine/glutamate antiporter xCT in immunogenic cell death and pre-metastatic niche modulation

Breast tumor accounts for the majority of cancer deaths in women, mainly due to the development of metastases. Historically considered immunologically inactive, it hinders the effectiveness of immunotherapy. Therefore, combining immunotherapy with strategies to activate the immune response in "cold" breast tumors holds promise. In addition, understanding the molecular and cellular mechanisms driving metastasis can facilitate the development of appropriate interventions. Inhibiting xCT, a protein overexpressed in breast cancer, can induce ferroptosis, recognized as a potential form of immunogenic cell death. However, it remains uncertain whether targeting xCT can render breast tumors more immunogenic and responsive to immune checkpoint blockade (ICB). Furthermore, xCT role in metastasis, possibly via non-cell-autonomous mechanisms, requires further elucidation. Our study reveals that pharmacological xCT inhibition in breast cancer cells induces ferroptosis and the release of damage-associated molecular patterns (DAMPs), potentially enhancing immunogenicity. However, in vivo efficacy of combining xCT inhibition and ICB remains unproven. Genetic xCT depletion affects the composition of the lung pre-metastatic niche, likely mediated by extracellular vesicles (EVs) with altered cargo due to xCT loss. EVs may thus play a role in xCT-dependent breast cancer metastasis, and xCT itself can be transported via EVs, potentially facilitating malignancy transmission. These findings suggest that targeting xCT could represent a promising approach in breast cancer treatment by enhancing immune responses and disrupting metastasis-supportive niche.