In neuroblastoma MYCN amplification is associated with enhanced angiogenesis and poor survival. Mutations in the anaplastic lymphoma kinase (ALK) gene can occur with MYCN amplification, conferring a very poor prognosis. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF)/c-MET signalling are implicated in neuroblastoma progression. Cabozantinib has potent activity against VEGFR2 and MET.
The efficacy of cabozantinib against tumours arising in GEM models of high-risk neuroblastoma was assessed using multiparametric MRI. Tumour-bearing Th-MYCN and Th-ALKF1174L/Th-MYCN mice were imaged prior to, 24 and 48 hrs after treatment with either 30mg/kg/day cabozantinib or vehicle. Treatment-induced changes in tumour volume, native T1, R2* and ADC were evaluated, and histological correlates sought. Additional Th-MYCN mice were treated daily for up to 28 days.
Cabozantinib elicited significant 24 and 60 % growth delay 24 and 48 hrs after treatment in tumours in Th-MYCN mice, and a significant 6-8 % reduction in native T1. Tumour R2* was significantly reduced 48 hrs post-treatment. Significantly higher tumour necrosis and apoptosis, and significantly lower Ki67, CD34 and VEGFR2 staining, was determined from the cabozantinib-treated mice. Treatment of Th-ALKF1174L/Th-MYCN mice caused significant 4 % and 21 % tumour growth delay, and a significant 5 % reduction in native T1 at 48 hrs. Daily cabozantinib treatment of Th-MYCN mice elicited significant tumour growth delay over 7 days which translated into significant survival benefit.
Cabozantinib exhibits activity against neuroblastomas arising in both Th-MYCN and Th-MYCN/ALKF1174L mice, revealed in situ using MRI. Native T1 is an early, sensitive and clinically translatable imaging biomarker of effective treatment response in neuroblastoma.
Copyright © 2025. Published by Elsevier Inc.

Peritoneal carcinomatosis is an advanced stage of cancer with very limited treatment options. Locoregional immunotherapy is being evaluated as a way to improve efficacy and limit toxicity. This study assessed the efficacy of a cationic polymer/lipid-based transfection compound in delivering mRNA molecules intraperitoneally. Our investigation of the transfer of luciferase mRNA in murine models of peritoneal carcinomatosis revealed preferential luciferase expression in the omentum upon the intraperitoneal administration of complexed mRNAs. Macrophages were identified as key cells that capture and express the mRNA complexes, and accordingly, depletion of resident macrophages led to reduced reporter luciferase expression. To explore the therapeutic potential of this approach, mRNA complexes encoding single-chain interleukin-12 (IL12), an immunostimulatory molecule (mRNA-IL12), were investigated. mRNA-IL12-treated mice exhibited a significant survival advantage in models of peritoneal carcinomatosis and acquired immune memory, as shown upon subcutaneous rechallenge. Tumor microenvironment analyses revealed increased numbers of CD4+ and CD8+ T cells with a more proliferative phenotype, accompanied by decreased myeloid populations in the omentum. Overall, our study underscores the potential of mRNA complexes for efficient mRNA delivery, eliciting effective antitumor responses and modulating the tumor microenvironment to treat peritoneal carcinomatosis.
© 2025. The Author(s).

This study sought to elucidate the mechanisms underlying the impact of the interferon signaling pathway on Ferroptosis in tumor cells and its correlation with CD8 + T cell exhaustion. Using mouse models and single-cell sequencing, the researchers studied the interaction between CD8 + T cells and the interferon signaling pathway. Differential gene analysis revealed key genes involved in CD8 + T cell exhaustion, and their downstream factors were explored using bioinformatics tools. The expression levels of interferon-related genes associated with Ferroptosis were analyzed using data from the TCGA database, and their relevance to tumor tissue Ferroptosis and patients' prognosis was determined. In vitro experiments were conducted to measure the levels of IFN-γ, MDA, and LPO, as well as tumor cell viability and apoptosis. In vivo validation using a mouse tumor model confirmed the results obtained from the in vitro experiments, highlighting the potential of silencing HSPA6 or DNAJB1 in enhancing the efficacy of PD-1 therapy and inhibiting tumor growth and migration.
© 2024. The Author(s).

Hepatocellular carcinoma (HCC) is a common malignant tumor with a complex immune evasion mechanism posing a challenge to treatment. The role of the S100A10 gene in various cancers has garnered significant attention. This study aims to elucidate the impact of S100A10 on CD8+ T cell exhaustion via the cPLA2 and 5-LOX axis, thereby elucidating its role in immune evasion in HCC. By analyzing the HCC-related data from the GEO and TCGA databases, we identified differentially expressed genes associated with lipid metabolism and developed a prognostic risk model. Subsequently, through RNA-seq and PPI analyses, we determined vital lipid metabolism genes and downstream factors S100A10, ACOT7, and SMS, which were significantly correlated with CD8+ T cell infiltration. Given the most significant expression differences, we selected S100A10 for further investigation. Both in vitro and in vivo experiments were conducted, including co-culture experiments of CD8+ T cells with MHCC97-L cells, Co-IP experiments, and validation in an HCC mouse model. S100A10 was significantly overexpressed in HCC tissues and potentially regulates CD8+ T cell exhaustion and lipid metabolism reprogramming through the cPLA2 and 5-LOX axis. Silencing S100A10 could inhibit CD8+ T cell exhaustion, further suppressing immune evasion in HCC. S100A10 may activate the cPLA2 and 5-LOX axis, initiating lipid metabolism reprogramming and upregulating LTB4 levels, thus promoting CD8+ T cell exhaustion in HCC tissues, facilitating immune evasion by HCC cells, ultimately impacting the growth and migration of HCC cells. This research highlights the critical role of S100A10 via the cPLA2 and 5-LOX axis in immune evasion in HCC, providing new theoretical foundations and potential targets for diagnosing and treating HCC.
© 2024. The Author(s).

Groundwater arsenic is a notorious toxicant and exposure to environmentally relevant concentrations persists as a healthcare burden across the world. Arsenic has been reported to jeopardize the normal functioning of the immune system, but there are still gaps in the understanding of thymic T cell biology. Immunotoxic influence of arsenic in thymic integrity demands a potent restorative molecule. The objectives of this study were to examine key signaling cross-talks associated with arsenic-induced immune alterations in the thymus and propose melatonin as a potential candidate against immunological complications arising from arsenic exposure. Swiss albino mice were exposed to sodium arsenite (0.05 mg/L; in drinking water) and melatonin (IP:10 mg/kg BW) for 28 days. Melatonin successfully protected thymus from arsenic-mediated tissue degeneration and maintained immune homeostasis including T cell maturation and proliferation by mitigating oxidative stress through Nrf2 upregulation. Additionally, melatonin exerted ameliorative effect against arsenic-induced apoptosis and inflammation by inhibiting p53-mediated mitochondrial cell death pathway and NF-κB-p65/STAT3-mediated proinflammatory pathway, respectively. For the first time, we showed that arsenic-induced profibrotic changes were inhibited by melatonin through targeting of inflammation-associated EMT. Our findings clearly demonstrate that melatonin can be a viable and promising candidate in combating arsenic-induced immune toxicity with no collateral damage, making it an important research target.
© 2024 International Union of Biochemistry and Molecular Biology.