Is System x_c^- a Suitable Target for Tumour Detection and Response Assessment with Imaging?

System x_c^- is upregulated in cancer cells and can be imaged using novel radiotracers, most commonly with (4S)-4-(3-[¹⁸F]fluoropropyl)-L-glutamic acid (¹⁸F-FSPG). The aim of this review was to summarise the use of ¹⁸F-FSPG in humans, explore the benefits and limitations of ¹⁸F-FSPG, and assess the potential for further use of ¹⁸F-FSPG in cancer patients. To date, ten papers have described the use of ¹⁸F-FSPG in human cancers. These studies involved small numbers of patients (range 1-26) and assessed the use of ¹⁸F-FSPG as a general oncological diagnostic agent across different cancer types. These clinical trials were contrasting in their findings, limiting the scope of ¹⁸F-FSPG PET/CT as a purely diagnostic agent, primarily due to heterogeneity of ¹⁸F-FSPG retention both between cancer types and patients. Despite these limitations, a potential further application for ¹⁸F-FSPG is in the assessment of early treatment response and prediction of treatment resistance. Animal models of cancer have shown that changes in ¹⁸F-FSPG retention following effective therapy precede glycolytic changes, as indicated by ¹⁸F-FDG, and changes in tumour volume, as measured by CT. If these results could be replicated in human clinical trials, imaging with ¹⁸F-FSPG PET/CT would offer an exciting route towards addressing the currently unmet clinical needs of treatment resistance prediction and early imaging assessment of therapy response.