Ontosight Newsletter Issue 24

Ontosight - Biweekly Newsletter

April 7th 2025 - April 20th, 2025 - Issue 24

Welcome to the 24th edition of Ontosight Newsletter! This issue features breakthroughs in oncology, neuroscience, CAR-T therapies, infectious diseases, and gut-mediated immune regulation. Discover novel targets, therapeutic strategies, and precision delivery systems transforming cancer and neurodegenerative care. Plus, explore global regulatory highlights, including key approvals in oncology, immunology, and rare diseases.

Featured Articles

1. Breakthroughs in Cancer & Oncology

• Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring

This study profiled high-risk neuroblastoma before and after chemotherapy using multi-omics to uncover changes in tumor and immune cell populations. Poor outcomes were linked to proliferative and metabolically active tumor states, while differentiated neuronal-like states predicted better prognosis. Therapy increased mesenchymal tumor cells and immunosuppressive, pro-angiogenic macrophages. The HB-EGF–ERBB4 signaling axis was identified as a key tumor-promoting interaction, highlighting regulators of therapy resistance and potential therapeutic targets Read More.

• Pan-cancer human brain metastases atlas at single-cell resolution

This study uses integrative single-cell RNA sequencing on 108 brain metastases (BrMs) and 111 primary tumors to uncover key features of BrM biology. Malignant BrM cells exhibit chromosomal instability, angiogenic activity, and a neural-like transcriptional program. The BrM microenvironment is dominated by immunosuppressive myeloid and stromal cells, linked to poor outcomes and immunotherapy resistance. Five BrM ecotypes were identified, offering insights into shared vulnerabilities that could guide future therapies Read More.

• SNX10 deficiency impairs sensitivity to anti-HER2 antibody-drug conjugates in HER2-positive breast cancer

This study identifies SNX10 deficiency as a key driver of resistance to anti-HER2 antibody-drug conjugates (ADCs) in HER2-positive breast cancer. SNX10 loss disrupts HER2 recycling by altering endosomal trafficking via RAB11A, leading to increased HER2 degradation in lysosomes and reduced surface HER2. These findings highlight a novel resistance mechanism and potential target to enhance ADC efficacy Read More.

• Sacituzumab tirumotecan in previously treated metastatic triple-negative breast cancer

The OptiTROP-Breast01 phase 3 trial showed that sacituzumab tirumotecan (sac-TMT) significantly improved progression-free survival (6.7 vs. 2.5 months) and overall survival over chemotherapy in heavily pretreated metastatic TNBC patients. Sac-TMT also had higher response rates (45.4% vs. 12%) and longer response duration. Hematologic toxicity was the main adverse effect. These results support sac-TMT as an effective treatment option for advanced TNBC Read More.

• Tumor microenvironment-responsive nanocarrier potentiates radionuclide therapy and chemotherapy

This study introduces a tumor-targeting drug delivery system combining radionuclide therapy and chemotherapy, guided by real-time MRI/SPECT imaging. The carrier, based on HA-HSA and loaded with doxorubicin and ^131I, targets CD44-overexpressing tumors and responds to the tumor microenvironment. It enables precise drug delivery, enhances therapeutic efficacy, and allows real-time monitoring. In vitro and in vivo tests confirmed its biocompatibility, tumor specificity, and significant tumor growth inhibition Read More.

2. Neuroscience & Neurodegenerative Disorders

• Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease

This study reveals that TIM-3, a genetic risk factor for late-onset Alzheimer's disease, regulates microglial homeostasis through TGFβ signaling. TIM-3 enhances SMAD2 phosphorylation by interacting with TGFBR2, maintaining microglial balance. Deletion of TIM-3 in microglia increases phagocytic activity, shifts gene expression toward a disease-associated microglial phenotype (MGnD), and reduces amyloid-β pathology in Alzheimer’s mouse models. These findings highlight TIM-3 as a potential therapeutic target in Alzheimer’s disease Read More.

• MLKL inhibitor reduces oxidative stress and neuronal cell death in Parkinson’s disease model

This study demonstrates that necrosulfonamide (NSA), a specific inhibitor of MLKL, protects against dopaminergic neuron loss in a Parkinson’s disease mouse model. NSA reduced neuroinflammation, oxidative stress, and microglial/astrocyte activation, while restoring neurotrophic factor expression. It inhibited MLKL phosphorylation, suggesting that blocking necroptosis may offer therapeutic potential for Parkinson’s disease by preserving neuronal health and reducing inflammation Read More.

• Exosome-shuttled miR-5121 from A2 astrocytes promotes BSCB repair after traumatic SCI by activating autophagy in vascular endothelial cells

This study highlights the therapeutic potential of exosomes derived from A2-type astrocytes (A2-Exos) in repairing the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI). A2-Exos were shown to enhance motor recovery, promote BSCB reconstruction, and induce endothelial cell autophagy. miRNA analysis identified miR-5121 as a key mediator, acting through the AKT2/mTOR/p70S6K pathway, suggesting a promising target for SCI treatment Read More.

• Gene signatures and immune correlations in Parkinson’s disease Braak stages

This study used weighted gene co-expression network analysis to identify 388 genes linked to Parkinson’s disease (PD) progression across Braak stages. Among eight hub genes found, CPLX2 emerged as the most reliable marker after validation across datasets. These genes are involved in key pathways like synaptic signaling and HIF-1 signaling. The study also uncovered stage-specific immune cell differences, highlighting CPLX2 as a potential therapeutic target and biomarker in PD Read More.

3. Immunotherapy & CAR-T Cell Therapy

• Anti-GPRC5D CAR T-cell therapy as salvage treatment in multiple myeloma

This phase 2 trial evaluated anti-GPRC5D CAR T-cell therapy in multiple myeloma patients who relapsed after anti-BCMA CAR T treatment. Among 37 treated patients, an impressive 84% overall response rate was observed, with 35% achieving complete response or better. The therapy was generally well tolerated, with manageable hematological toxicities and cytokine release syndrome. These findings suggest anti-GPRC5D CAR T cells could be a promising salvage option for resistant multiple myeloma Read More.

• Engineering TCR-controlled fuzzy logic into CAR T cells for enhanced specificity

Dual-receptor T cells co-expressing both CAR and TCR were engineered to improve specificity and potency in solid tumors. Strong TCR-antigen interactions enhanced CAR activation, while weak interactions suppressed it, revealing a tunable crosstalk. These dual T cells targeting HER2 and neoantigens showed superior tumor-killing with minimal healthy tissue toxicity in mouse models. This strategy offers a new avenue for designing safer, more precise cancer immunotherapies Read More.

• Combination radiation and αPD-L1 therapy stimulates CD8+ TCF-1+ T cells

This study in murine melanoma models shows that combining radiotherapy (RT) with anti-PD-L1 therapy enhances tumor control by increasing progenitor CD8+ PD-1+ TCF-1+ T cells in tumors. These cells originate from tumor-draining lymph nodes (TdLN) and differentiate into effector-like cells upon trafficking to tumors. The combination also induces a novel migratory subset (PD-1+ TCF-1+ TOX- LY6A+) linked to type I interferon signaling. Ablation of this T cell population reduced therapeutic efficacy, suggesting its critical role in mediating abscopal responses Read More.

• BIRC2 blockade enhances immunotherapy in hepatocellular carcinoma

This study identifies BIRC2 as a key driver of immune evasion in hepatocellular carcinoma (HCC). BIRC2 suppresses the non-canonical NFκB pathway by degrading NIK, leading to reduced MHC-I expression and resistance to T cell-mediated killing. Blocking BIRC2 sensitized tumor cells to immune attack and enhanced T cell function, improving the response to anti–PD-1 therapy. Targeting BIRC2 offers a promising strategy to boost immunotherapy effectiveness in HCC Read More.

4. Infectious Diseases & Antimicrobial Research

• Prediction and evaluation of coronavirus-human protein-protein interactions

This study developed a unified computational model combining five methods—including interolog mapping and machine learning—to predict protein-protein interactions (PPIs) between coronaviruses and human proteins. The model showed strong performance on practical datasets (C2v and C3) and identified 18,012 high-confidence interactions involving 3843 human and 129 viral proteins. These findings offer new insights into coronavirus-host interactions and potential antiviral targets. The data and code are publicly available on GitHub Read More.

• Microvesicles carrying EV71 virions cross BBB to induce brain injury

This study reveals that microvesicles (MVs) carrying Enterovirus 71 (EV71) enhance viral transmission across the blood-brain barrier (BBB) and contribute to severe neurological complications. MVs facilitate EV71 entry via a non-clathrin-dependent mechanism and deliver damaged mitochondria, which worsen brain injury by triggering apoptosis and oxidative stress. The findings highlight a novel mechanism in EV71 neuropathogenesis and suggest potential therapeutic targets for viral encephalitis Read More.

• Dimethyl itaconate alleviates E. coli-induced endometritis via CXCL14 axis

This study shows that dimethyl itaconate (DI) alleviates E. coli-induced endometritis in mice through gut microbiota modulation. The protective effect is dependent on the presence of gut microbes, especially Muribaculum intestinale, which increases uterine guanosine levels. Guanosine, in turn, activates CXCL14 expression in uterine epithelial cells to reduce inflammation. These findings highlight a gut-uterus axis and suggest DI as a promising therapeutic via microbiota-mediated pathways.Read More.

5. Gut-Mediated Immune and Metabolic Regulation

• Protein-responsive gut hormone tachykinin influences food choice and lifespan

This study identifies tachykinin (Tk) as a gut hormone activated by protein intake in both Drosophila and mice. Protein stimulates Tk release via TOR and TrpA1 pathways in enteroendocrine cells, influencing appetite and behavior through AKH signaling. Gut Tk suppresses protein hunger, promotes sugar craving, alters sleep, and, when inhibited, extends lifespan. These findings reveal a conserved gut-brain axis linking nutrient sensing to food choice, sleep, and longevity Read More.

• Gut commensal Bifidobacterium-derived vesicles enhance anti-PD-1 lung cancer therapy

This study shows that extracellular vesicles from commensal Bifidobacterium (Bif.BEVs) enhance anti-PD-1 immunotherapy in non-small cell lung cancer (NSCLC). Bif.BEVs are taken up by lung cancer cells via dynamin-dependent endocytosis and activate the TLR4-NF-κB pathway to increase PD-L1 expression. Oral delivery of Bif.BEVs leads to tumor accumulation and boosts immune response, including CD8+ T cell infiltration. These findings reveal how gut microbiota can remotely modulate lung tumor microenvironments and improve immunotherapy efficacy Read More.

• Time-restricted feeding protects against septic liver injury via gut microbiota modulation

This study reveals that time-restricted feeding (TRF) alleviates septic liver injury by reshaping gut microbiota, specifically boosting Lactobacillus murinus levels. L. murinus increases 3-hydroxybutyrate (3-HB) production, which activates the PI3K/AKT/mTOR/LPIN1 pathway to inhibit hepatocyte ferroptosis. Knocking out the 3-HB-producing enzyme (Hmgcs2) nullifies the benefit. These findings position 3-HB as both a therapeutic target and predictive biomarker for septic liver injury, offering new avenues for treatment and diagnosis Read More.

Additional Highlights

Explore more groundbreaking research and regulatory updates in our biweekly newsletter:

• Legumain In Situ Engineering Promotes Efferocytosis of CAR Macrophage to Treat Cardiac Fibrosis

• GABAergic neurons in central amygdala contribute to orchestrating anxiety-like behaviors and breathing patterns

• KalVista Pharmaceuticals Enters Into Licensing Agreement With Kaken Pharmaceutical to Commercialize Sebetralstat for HAE in Japan

• U.S. Food and Drug Administration Updates CAMZYOS® (mavacamten) Label to Reduce Echocardiography Monitoring Requirements and Contraindications

• Biocon Biologics Secures Market Entry Date for Yesafili™, an Interchangeable Biosimilar to Eylea®, in the U.S.

• Regeneron Provides Update on EYLEA HD® (aflibercept) Injection 8 mg Supplemental Biologics License Application

• GSK’s 5-in-1 meningococcal vaccine Penmenvy receives positive recommendation from US Advisory Committee on Immunization Practices

• Arexvy recommended for adults aged 50-59 at increased risk for severe respiratory syncytial virus (RSV) disease by US Advisory Committee on Immunization Practices