Justin D. Lathia

The surgical margin is the primary site of glioblastoma recurrence, yet its molecular features remain poorly characterized. We performed histology-guided sampling and single-cell spatial transcriptomics of surgical margin and adjacent recurrent tumor regions, with matched primary tumors from 40 patients. The surgical margin constituted a distinct wound-healing microenvironment in the post-treatment setting. We also identified malignant states with pronounced mesenchymal transcriptomic and histological features that were enriched at the surgical margin and defined a "stromal" subtype. Patients who transitioned to this subtype at recurrence were characterized by early TP53 mutation, sustained proliferation during adjuvant temozolomide treatment, and shorter survival. Conversely, patients with TP53-wild-type tumors recurring during temozolomide treatment transitioned toward the mesenchymal subtype, with increased p53 pathway activity and reduced proliferation. Functional validation showed TP53 loss-of-function increased temozolomide resistance in a patient-derived glioblastoma model. Our findings identify distinct glioblastoma recurrence trajectories linked to genomic context, treatment exposure, and clinical outcomes.

Glioblastoma (GBM) adapts to metabolic stress through mitochondrial pathways that are not fully defined. Here, we show sulfide quinone oxidoreductase (SQOR) is upregulated in human GBM and functions as a mitochondrial checkpoint linking hydrogen sulfide (H ₂ S) clearance to electron transport chain activity. In patient-derived GBM cells and immunocompetent syngeneic tumors, SQOR channels H ₂ S-derived electrons into the ubiquinone pool to sustain oxidative phosphorylation during stress. Genetic or pharmacologic SQOR inhibition causes intracellular H ₂ S accumulation, collapse of mitochondrial respiration, tricarboxylic acid cycle dysfunction, and compensatory glycolytic engagement. SQOR loss also redirects carbon into lipid synthesis and storage while impairing lipid mobilization, thereby limiting metabolic flexibility and stem-like cell maintenance. Increasing endogenous H ₂ S production further exacerbates the bioenergetic defects caused by SQOR blockade. Functionally, genetic or pharmacologic SQOR inhibition suppresses tumor growth and prolongs survival in vivo . Together, these data identify SQOR-dependent sulfide oxidation as a mitochondrial liability that supports GBM metabolic plasticity.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying distinct immune-cancer interactions are poorly understood. Here we identify γ-aminobutyric acid (GABA) as a female-specific driver of GBM-promoting immune response. We demonstrated that GABA receptor B (GABBR) signaling enhances the T cell suppressive function of granulocytic myeloid-derived suppressor cells (gMDSCs) from female mice by upregulating the cationic amino acid transporter 2–L-arginine–nitric oxide synthase 2 (NOS2) pathway. GABBR agonism promotes GBM growth in female preclinical models through gMDSCs, while GABBR antagonism extends survival and reduces NOS2 in tumor-infiltrating gMDSCs only in female mice. Immune cells from female participants with GBM have enriched GABA transcriptional signatures and a higher GABA concentration compared to male counterparts. Collectively, these results highlight the sex-specific immunomodulatory role of GABA in tumorigenesis, supporting future assessment of GABA pathway inhibitors for cancer immunotherapy.

Dissecting and Targeting the Heterogeneity and Plasticity of the Tumor Ecosystem

BACKGROUND: Despite antiplatelet therapy, some patients remain at high ischemic risk because of drug nonresponsiveness or high residual platelet reactivity. We aimed to target an orphan platelet GPCR (G protein–coupled receptor) from the OR (olfactory receptor) family as a novel antithrombotic strategy. METHODS: Using an engineered reporter cell line expressing human OR2L13 , an orphan GPCR implicated in limiting platelet reactivity, we conducted a high-throughput screen of 8000 nonodorant bioactive compounds with counterscreen validation. Subsequent studies assessed platelet function in healthy subjects and patients with coronary artery and peripheral artery disease. Phospho-proteomics revealed key signaling pathways, whereas ex vivo and in vivo studies evaluated the impact of a lead compound on platelet signaling, biomechanics, and thrombosis in both arterial and venous vasculature. RESULTS: We identified 6 OR2L13 (olfactory receptor family 2 subfamily L member 13)-specific agonists that suppressed platelet aggregation and α-granule exocytosis through multiple receptors, suggesting a shared downstream mediator. The lead agonist (CCF0054500) phosphorylated platelet HSP27 (heat shock protein 27), disrupting the actin cytoskeleton and reducing clot retraction (clot area, 70.6 versus 5.2; P P P P =0.007). CONCLUSIONS: We describe and characterize the first nonolfactory probe for the purpose of inhibiting platelet activation and thrombosis through downstream HSP27 in a comprehensive investigation using a first-of-its-kind platelet inhibitor targeting an orphan platelet GPCR.

Sex differences in antitumor immunity contribute to disparities in cancer outcomes, yet the role of CD4+ T helper cells in this context remains poorly understood. In this issue, Hunt and colleagues show that sex hormones restrain CD4+ T-cell help in males, weakening antitumor immune responses and promoting tumor progression. This work identifies CD4+ T-cell help as a previously underappreciated driver of sex-biased cancer immunity, with potential implications for sex-informed immunotherapy strategies. See related article by Hunt et al., p. XX .