BACKGROUND: Cabozantinib, a tyrosine kinase inhibitor (TKI) approved for advanced hepatocellular carcinoma (HCC), has established clinical benefit although the underlying immunomodulatory mechanisms, particularly those involving mitochondrial stress and the cGAS/STING pathway, remain poorly defined. METHODS: We assessed cabozantinib’s effects on mitochondrial integrity and innate immune signaling in hepatoma cells and macrophage cell lines, analyzing mitochondrial depolarization, reactive oxygen species production, cytosolic release of mitochondrial DNA (mtDNA), activation of the cGAS/STING pathway and induction of type I interferon-stimulated genes (ISGs). Functional relevance was tested by mtDNA depletion and CRISPR-mediated STING knockdown. The in vivo effects of cabozantinib and the STING agonist DMXAA were examined in immunocompetent mouse models. Translational relevance was evaluated by multiplex proteomic profiling of serum samples from 18 cabozantinib-treated HCC patients across two independent cohorts. RESULTS: Cabozantinib induced mitochondrial depolarization, oxidative stress, and cytosolic mtDNA release, resulting in STING-dependent signaling and ISG upregulation in hepatoma cells. Disruption of mtDNA or STING abrogated these effects. In vivo, cabozantinib reduced tumor growth and promoted tumor-infiltrating lymphocyte activation, which were further enhanced by DMXAA co-treatment. Patient serum proteomics revealed consistent increases in immune and stress-related proteins (e.g., granzyme B, HO-1, CAIX, CXCL13) and decreases in angiogenic and immunosuppressive factors (e.g., VEGFR-2, ANGPT1/2, CCL17), paralleling the systemic immune remodeling observed in preclinical models. Both baseline immune signatures and treatment-induced protein shifts were associated with clinical outcome. CONCLUSIONS: Cabozantinib promotes tumor immunogenicity through mitochondrial disruption and cGAS/STING activation, leading to immune remodeling in HCC. These findings provide mechanistic insight into the immunomodulatory effects of cabozantinib, support rational combinations with STING agonists, and highlight candidate biomarkers for predicting therapeutic response in TKI-treated patients.
Slow waves (SWs), the hallmark of non-rapid eye movement (NREM) sleep, reflect the periodic occurrence of transient silent periods in cortical neurons (Down states). During NREM, SWs and Down states physiologically disrupt large-scale network interactions. Since early EEG studies, SWs have also been observed in awake patients after brain injury. Emerging evidence indicates that these intrusions of sleep-like activity interfere with ongoing network activity and contribute to motor and cognitive deficits; yet, the mechanisms governing the generation and spread of post-lesional SWs remain unclear. Here, we extend a neural mass model of EEG to capture transitions between wake-like and sleep-like dynamics and embed it in connectome-based networks with virtual lesions. This model supports that local disfacilitation, topology-dependent propagation, and synchrony-dependent amplification throughout the connectome are sufficient to produce post-lesional SWs. These mechanisms reproduce the spatial gradients of post-lesional SWs previously reported in patient studies, and identify actionable targets for neuromodulation and rehabilitation.
Abstract Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy with notable genetic, epigenetic, and clinical heterogeneity. In this study, we used coding and noncoding sequencing (n = 74), including whole-genome sequencing (WGS) of 24 paired tumor-normal samples, targeted sequencing (n = 55), and DNA methylation in 126 patients to characterize the disease. From WGS, we identified recurrent, predominantly clonal coding mutations in KLF2 (50%), KMT2D (25%), and NOTCH2 (25%), alongside rare mutations in FLNC (8%), novel mutations in FAM135B (17%), and noncoding mutational hot spots in BCL6, PAX5, and BACH2 linked to aberrant somatic hypermutation. At least 1 noncoding hot spot was detected in 69% of patients. Copy number aberrations were present in 73% of patients, including del(7q) (27%), gain(3q) (17%), and trisomy 12 (13%). DNA methylation profiling revealed 2 epigenetic subgroups: high-risk (HR) SMZL (n = 67) and low-risk SMZL (n = 59). SMZL-HR was associated with adverse features, including female sex, IGHV1-2∗04 usage, KLF2 mutations, del(7q), shorter telomeres, and elevated epigenetically determined cumulative mitoses scores. Transcriptomic analysis highlighted enhanced cell proliferation in SMZL-HR, with enrichment of E2F and G2M checkpoint pathways and epigenetic regulation via EZH2. Patients with SMZL-HR had significantly shorter time to first treatment (TTFT) (hazard ratio, 1.9; P = .003) and reduced overall survival (hazard ratio, 2.5; P = .039): 85% of patients with SMZL-HR required treatment and showed a higher frequency of transformation (P = .007) and mortality (P< .001). Multivariate analysis confirmed SMZL-HR as an independent predictor of shorter TTFT (hazard ratio, 2.4; P = .001). These findings demonstrate the role of DNA methylation and molecular profiling in SMZL risk stratification.
High-grade B-cell lymphoma with 11q-aberration (HGBCL-11q) is a rare pediatric non-Hodgkin lymphoma. This study assessed outcome in 90 children with HGBCL-11q. With survival rates ≥95%, patients with HGBCL-11q and no predisposition are candidates for deescalated therapy in future prospective trials.
Cardiac fibroblasts (CFs) are resistant to stress-induced death, a property important for tissue repair but also central to pathological fibrosis and heart failure. Comparative transcriptomic and proteomic analyses identified the mTOR-interacting protein DEPTOR as selectively enriched in CFs. Although DEPTOR is widely characterized as an inhibitor of mTORC1 and mTORC2 in tumor and immortalized cells, its role in differentiated somatic cells remains unclear. Here, we show that CFs display a context-dependent DEPTOR-mTOR signaling configuration in which DEPTOR sustains, rather than inhibits, mTOR-dependent outputs. DEPTOR silencing in adult CFs attenuates mTORC1 signaling with branch-specific sensitivity and strongly reduces BCL2, an integrative survival output of mTORC1/2 signaling. This leads to impaired α-smooth muscle actin induction and reduced fibroblast survival under stress, while AKT Ser473 phosphorylation remains comparatively buffered. Pharmacological dissection of the PI3K-mTOR axis supports DEPTOR as a stabilizer of this pro-survival network. Importantly, fibroblast-specific DEPTOR knockdown in vivo limits post-infarction fibrosis and preserves cardiac function. These findings redefine DEPTOR function in a differentiated somatic cell type, revealing a context-dependent mode of mTOR regulation shaping fibroblast behavior during cardiac injury.
