Ontosight Newsletter Issue 23

Ontosight – Newsletter

March 24th – April 6th, 2025 – Issue 23

Welcome to the 23nd edition of Ontosight Newsletter! This issue features cutting-edge research in cancer biology, neurodegeneration, metabolic and cardiovascular health, and immune-driven diseases. Discover novel biomarkers, therapeutic targets, and delivery strategies shaping precision medicine. Plus, explore key global regulatory updates, including approvals in oncology, rare diseases, and vaccine innovations.

Featured Articles

1. Cancer Biology & Oncology

• Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion

This study uncovers how arginine metabolism shapes a pro-tumor environment in breast cancer by driving metabolic crosstalk between cancer cells and macrophages. Cancer cells supply arginine, which polarizes tumor-associated macrophages (TAMs) to suppress CD8+ T cell activity. This interaction overrides arginine's direct benefits on T cells. Targeting the arginine-polyamine-TDG axis significantly hinders tumor growth, offering a promising therapeutic strategy. [Article]

• Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures

This study investigates the maturation of tertiary lymphoid structures (TLSs) in hepatocellular carcinoma using near single-cell spatial transcriptomics. It identifies two types of immature TLSs—conforming and deviating—based on their developmental trajectories. A tryptophan-rich metabolic environment, driven by malignant cells, impairs TLS maturation. Inhibiting tryptophan metabolism enhances TLS maturation and improves response to anti-PD-1 therapy, suggesting a novel approach to boost immunotherapy efficacy. [Article]

• Prognostic and immunotherapeutic potential of disulfidptosis-associated signature in pancreatic cancer

This study explores the role of disulfidptosis in pancreatic ductal adenocarcinoma (PDAC) by integrating multi-omics data. Researchers identified an 8-gene disulfidptosis-related prognostic signature, which correlates with poor prognosis and reduced response to immune checkpoint inhibitors. The signature is linked to tumor-promoting interactions between cancer-associated fibroblasts (myCAFs) and tumor cells. These findings highlight a novel biomarker for risk stratification and potential therapeutic targeting in PDAC. [Article]

• Reprogramming of glucose metabolism by nanocarriers to improve cancer immunotherapy

This review explores how targeting tumor glucose metabolism can enhance cancer immunotherapy by reversing immunosuppressive conditions in the tumor microenvironment. It highlights nanocarrier-based strategies to deliver glucose metabolism modulators—such as glycolytic enzyme inhibitors and oxidases—and their synergistic use with therapies like chemo-, radio-, and phototherapy. The article also discusses current challenges and future prospects of nanotechnology in metabolic reprogramming to boost immunotherapy outcomes. [Article]

• Pan-cancer analysis reveals MTTP as a prognostic and immunotherapeutic biomarker

This pan-cancer study identifies MTTP as a potential prognostic and immunotherapeutic biomarker, showing its elevated expression in many tumors and association with poor prognosis. MTTP is highly expressed in immune cells, particularly macrophages, and is linked to immune infiltration and checkpoint expression. In gastric cancer, MTTP promotes tumor progression and suppresses ferroptosis, with knockdown enhancing ferroptosis sensitivity. These findings suggest MTTP as a promising target for cancer therapy. [Article]

2. Neuroscience & Neurodegenerative Disorders

• Early increase of the synaptic blood marker β-synuclein in asymptomatic autosomal dominant Alzheimer’s disease

This study highlights blood β-synuclein as a promising early biomarker for Alzheimer's disease (AD). Levels were elevated in asymptomatic AD mutation carriers and highest in symptomatic individuals, rising up to 11 years before symptom onset. The increase in β-synuclein precedes axonal degeneration and cognitive decline, suggesting its potential for early diagnosis, tracking disease progression, and guiding clinical trials. [Article]

• Intranasal delivery of BDNF-loaded small extracellular vesicles for treating acute spinal cord injury

This study demonstrates that intranasally delivered small extracellular vesicles (sEVs) loaded with brain-derived neurotrophic factor (BDNF) significantly enhance recovery after acute spinal cord injury (SCI). In both rats and monkeys, BDNF-sEVs reduced inflammation, promoted neuronal survival and axonal rewiring, and improved motor function. These effects were linked to activation of the BDNF/TrkB signaling pathway, positioning BDNF-sEVs as a promising non-invasive therapeutic strategy for acute SCI treatment. [Article]

• Identification of Common Brain Protein and Genetic Loci Between Parkinson's Disease and Lewy Body Dementia

This study identifies shared genetic and protein risk factors between Parkinson's disease (PD) and Lewy body dementia (LBD) using proteome-wide association and GWAS analyses. TMEM175 and DOC2A emerged as common risk proteins, with TMEM175 consistently downregulated across PD and LBD patient samples. These findings highlight TMEM175 as a potential key player in the comorbidity of PD and LBD, shedding light on their shared genetic basis. [Article]

• Foundation model of neural activity predicts response to new stimulus types

This study presents a foundation model trained on large-scale neural activity data from mouse visual cortices, capable of accurately predicting neuronal responses to diverse natural video stimuli. The model generalizes across individual mice and new stimulus types with minimal retraining. It also predicts cell types, dendritic features, and neuronal connectivity, marking a significant step toward brain-wide foundation models. Such models promise to enhance our understanding of neural computation and accelerate neuroscience research. [Article]

• Amyloid precursor protein and presenilin-1 knock-in mice exhibit intraneuronal Aβ and microgliosis

This study introduces novel Alzheimer's disease knock-in mouse models (NA and NAPS) with familial AD mutations on an immunodeficient NOG background, enabling human immune system studies. These models replicate AD-like pathology without overexpression artifacts, including intraneuronal amyloid-β deposition, microgliosis, and neuronal loss. The addition of the PS1 mutation enhances amyloid burden. These models offer a valuable platform for testing AD immunotherapies and studying immune-related comorbidities. [Article]

3. Metabolism, Obesity & Endocrinology

• GLP-1 receptor agonist-based therapies on cardiovascular events in obese individuals without diabetes

This meta-analysis of 29 RCTs involving nondiabetic adults with overweight or obesity found that GLP-1RA-based therapies significantly reduce total cardiovascular events, myocardial infarction, and all-cause mortality. These therapies also improved key cardiometabolic parameters, with specific agents like tirzepatide and semaglutide showing strong effects on BMI, HbA1c, lipid profile, and inflammation. The results support the cardioprotective potential of GLP-1RAs in this population. [Article]

• Glycated hemoglobin and BMI as mediators of GLP-1RAs and Alzheimer’s disease in patients with type 2 diabetes

This cohort study of over 22,000 adults with type 2 diabetes found that GLP-1 receptor agonists (GLP-1RAs) significantly reduced the risk of Alzheimer's and related dementias (ADRD) by 26% compared to other glucose-lowering drugs. While GLP-1RAs also modestly lowered HbA1c and BMI, these reductions had minimal impact on dementia risk, suggesting the neuroprotective effect is largely independent of metabolic changes. [Article]

• Interaction of underweight, low muscle mass, and inflammation on mild cognitive impairment in T2DM

This study examined how body composition and nutritional inflammatory markers impact early-onset mild cognitive impairment (EOMCI) in patients with type 2 diabetes. A low body composition and poor nutritional-inflammatory profile were linked to a higher EOMCI risk, with abdominal obesity and low muscle mass significantly compounding the risk when combined with malnutrition. Overall, healthier indices were associated with a 31.3% lower EOMCI risk. The findings highlight the need for integrated management of nutrition, inflammation, and body composition to reduce cognitive decline in T2DM. [Article]

4. Cardiovascular & Renal Health

• Common-variant and rare-variant genetic architecture of heart failure

This study identifies 176 common genetic loci and several rare loss-of-function variants (in genes like TTN, MYBPC3, FLNC, and BAG3) associated with heart failure across over 2 million individuals. Common variants contribute to heart failure risk via diverse biological pathways, while rare variant heritability is concentrated in key cardiomyopathy genes. Importantly, polygenic risk modifies the impact of rare mutations, revealing genetic complexity beyond current clinical testing. [Article]

• NAD(+) boosting increases atherosclerotic plaques and inflammation in Apoe knockout mice

This study investigated the effects of high-dose nicotinamide riboside (NR), a NAD+ precursor, on atherosclerosis in Apoe knockout mice. Contrary to expectations, high NR doses increased aortic plaque formation, inflammation, and LDL-cholesterol levels. These pro-atherogenic effects were linked to altered NAD+ metabolism favoring CD38 and PARP1 pathways over sirtuin activation. The findings raise concerns about using NAD+ boosters like NR in individuals with atherosclerosis. [Article]

• Clinical efficacy and safety of GLP-1 RA, SGLT-2 inhibitors, and Finerenone in T2DM with CKD

This meta-analysis of 39 studies (99,599 patients) assessed the efficacy and safety of SGLT-2 inhibitors, GLP-1 receptor agonists, and Finerenone in T2DM patients with non-dialysis CKD. SGLT-2 inhibitors were most effective in lowering HbA1c, body weight, and blood pressure. GLP-1 agonists, particularly Liraglutide, significantly reduced LDL-C, while Finerenone effectively lowered systolic BP with minimal urinary tract infection risk. Overall, all three drug classes were deemed safe, with varying benefits across metabolic and cardiovascular parameters. [Article]

• Mechanistic evaluation of ertugliflozin in T2DM and heart failure

This study evaluated the effects of SGLT2 inhibitor ertugliflozin on fluid balance and kidney function in type 2 diabetes patients with heart failure. Ertugliflozin increased sodium excretion and urine volume at 1 week, with reduced extracellular and plasma volume by 12 weeks. Though natriuretic effects were not mediated by proximal tubular mechanisms, the drug shifted volume status toward euvolemia and lowered blood pressure, supporting its potential to reduce heart failure risk. [Article]

5. Immunology, Autoimmune & Inflammation

• Ibrutinib biases T cell responses to sustain inflammation in chronic lymphocytic leukemia

This study shows that exposure to staphylococcal superantigens (SAgs) in chronic lymphocytic leukemia (CLL) patients, especially those treated with ibrutinib, leads to dysfunctional T cells with an exhaustion-like phenotype and enhances inflammatory activation of CLL tumor cells. Ibrutinib fails to counteract these effects. The findings suggest that SAgs contribute to chronic inflammation, impaired immunity, and increased infection risk in CLL, offering insights into disease progression and therapeutic challenges. [Article]

• Effects of anti-CD20 therapy on immune cell dynamics in multiple sclerosis

This study analyzed immune cell dynamics in RRMS patients treated with ocrelizumab or ofatumumab. Both therapies led to depletion of CD20+ B and T cells, increased regulatory T cells, and elevated exhaustion markers (e.g., TIGIT) across immune subsets. A rise in CD5+ B cells and a reduction in double-negative T cells—associated with MS activity—were also observed. These immune shifts correlated with clinical outcomes, highlighting their potential relevance to MS pathogenesis and treatment response. [Article]

• Albumin nanoassembly manipulates ferroptosis in TNBC

This study presents LHS nanoparticles—engineered from hemin, linoleic acid-cystamine, and a CD36 inhibitor—as a dual-action strategy for triple-negative breast cancer (TNBC) therapy. These nanoparticles enhance ferroptosis in tumor cells while protecting CD8+ T cells by inhibiting CD36-mediated lipid peroxidation. This approach boosts immunotherapy efficacy by promoting immunogenic cell death, enhancing T and NK cell responses, and reshaping the tumor microenvironment. The result is significant tumor suppression and reduced lung metastasis in TNBC models. [Article]

• Epinephrine vs. norepinephrine in pediatric septic shock

This retrospective cohort study compared epinephrine and norepinephrine as first-line vasoactive agents in pediatric septic shock without cardiac dysfunction. Among 231 patients, epinephrine was associated with higher 30-day mortality (4.1% vs 0%) but showed no significant difference in major adverse kidney events (MAKE30) compared to norepinephrine. These findings suggest norepinephrine may be a safer initial choice, warranting further prospective studies. [Article]

Additional Highlights

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

Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation [Article]

FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature[Article]

GSK’s application to expand use of Nucala (mepolizumab) for the treatment of COPD accepted for review by the European Medicines Agency[News]

Amneal Announces Expanded Coverage for CREXONT® (Carbidopa and Levodopa) to Enhance Access for Parkinson’s Disease Patients in the U.S.[News]

Amneal Launches BORUZU™, First Ready-to-Use Bortezomib Injection for Multiple Myeloma and Mantle Cell Lymphoma[News]

European Commission Approves Pfizer’s RSV Vaccine ABRYSVO® to Help Protect Adults Aged 18-59 Against RSV Lower Respiratory Tract Disease[News]

Update on U.S. FDA BLA for Novavax's COVID-19 Vaccine[News]

Aldeyra Therapeutics Receives Complete Response Letter from the U.S. Food and Drug Administration for the Reproxalap New Drug Application for the Treatment of Signs and Symptoms of Dry Eye Disease[News]