Thiol Scarcity in Cerebrospinal Fluid Renders Leptomeningeal Acute Lymphoblastic Leukaemia Therapeutically Vulnerable to Ferroptosis

The leptomeninges present a challenging tumour microenvironment with cells receiving low levels of nutrients and oxygen from cerebrospinal fluid (CSF), however these metabolic constraints are yet to be exploited therapeutically. Central nervous system (CNS) relapse in acute lymphoblastic leukaemia (ALL) remains a formidable clinical challenge because the leptomeningeal niche restricts drug penetration and immune surveillance. Current CNS-directed treatments rely on neurotoxic intrathecal chemotherapy, underscoring the urgent need for novel targeted strategies. Here, we uncover a profound niche-specific metabolic vulnerability in CNS-resident ALL cells, characterised by an obligate reliance on LRP8-mediated selenium uptake to sustain selenocysteine biosynthesis and GPX4 activity under profound glutathione limitation. We show that scarcity of thiols and cystine in CSF creates an inherently pro-ferroptotic microenvironment. Interference with selenocysteine biosynthesis under these conditions induces synthetic lethality in both in vitro and in vivo CNS-ALL models. This vulnerability is exploitable both by genetic targeting of the selenocysteine biosynthesis pathway and, notably, through repurposing the FDA-approved agent Auranofin, which disrupts selenium utilisation, induces lipid peroxidation, and demonstrates CNS-specific anti-leukaemic eaicacy with excellent tolerability in vivo. These findings identify a novel mechanistically grounded approach, leveraging features of the unique leptomeningeal microenvironment to selectively kill invading cells, with potential implications for all leptomeningeal-tropic malignancies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/693383v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@2303dforg.highwire.dtl.DTLVardef@d357ceorg.highwire.dtl.DTLVardef@129cb26org.highwire.dtl.DTLVardef@d83183_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO The leptomeningeal tumour microenvironment is intrinsically pro-ferroptotic due to low concentrations of free thiols and cystine in cerebrospinal fluid. ALL cells in this niche exhibit disrupted glutathione metabolism and a novel dependency on LRP8-mediated SELENOP uptake to sustain GPX4 levels and thus protect themselves from spontaneous ferroptotic cell death. Perturbation of selenocysteine biosynthesis via genetic inhibition SEPHS2 or LRP8 leads to synthetic lethality in leukaemic cells exposed to CSF in vitro and in vivo - an effect phenocopied by use of Auranofin. C_FIG