Ontosight Newsletter Issue 28

Ontosight - Biweekly Newsletter

June 16th, 2025 - June 29th, 2025 - Issue 28

Welcome to the 28th edition of the Ontosight Newsletter! This issue brings together the latest breakthroughs across cancer immunotherapy, oncology innovations, cell and gene therapies, neuroscience, cardiometabolic health, and computational medicine. Explore how advances in immune modulation, precision biomarkers, neurodegeneration, and AI-powered multi-omics are redefining therapeutic frontiers and accelerating clinical translation.

Featured Articles

1. Cancer Immunotherapy and the Tumor Microenvironment

• Bile acids activate cancer-associated fibroblasts and induce an immunosuppressive microenvironment in cholangiocarcinoma

This study reveals that high bile acid levels in cholangiocarcinoma (CCA) activate GPBAR1 on cancer-associated fibroblasts, increasing CXCL10 expression. This promotes cancer metastasis and creates an immunosuppressive environment by attracting neutrophils. Blocking the GPBAR1-CXCL10 pathway enhances the effect of pembrolizumab in CCA models, identifying it as a potential target to improve immunotherapy outcomes. Read More

• Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer

This study shows that the p53R172H mutation in pancreatic ductal adenocarcinoma (PDAC) promotes tumor growth and immune evasion by upregulating the immunosuppressive chemokine Cxcl1. The mutant p53 binds to Cxcl1 enhancers via the NF-κB pathway, creating an immunosuppressive tumor microenvironment and reducing the effectiveness of immune checkpoint inhibitors. Read More

• Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti-PD-1 resistance in hepatocellular carcinoma

This study identifies Riplet silencing as a key mechanism of immunotherapy resistance in hepatocellular carcinoma (HCC). Loss of Riplet enhances fatty acid production via FASN, leading to CD8 T cell exhaustion through STAT3 palmitoylation. Riplet-deficient tumors resist anti-PD-1 therapy, but this can be reversed with FASN inhibitors, offering a potential combination strategy for treating resistant HCC. Read More

• Hepatitis B virus promotes liver cancer by modulating the immune response to environmental carcinogens

This study shows that HBV alone doesn't directly cause liver inflammation or cancer but enhances the effects of environmental carcinogens like DEN to promote liver cancer. The IL-33/regulatory T cell axis plays a key role in this process. Inhibiting IL-33 with pitavastatin reduces cancer risk, highlighting a potential preventive strategy for HBV carriers exposed to carcinogens. Read More

• A CXCR4 partial agonist improves immunotherapy by targeting immunosuppressive neutrophils and cancer-driven granulopoiesis

This study shows that a CXCR4 partial agonist (TFF2-MSA) enhances anti-PD-1 immunotherapy by reducing immunosuppressive neutrophils and granulopoiesis in gastric cancer models. Unlike CXCR4 antagonists, TFF2-MSA selectively depletes CXCR4⁺ suppressive neutrophils, improving CD8⁺ T cell responses and reducing tumors and metastases, offering a new strategy to overcome immunotherapy resistance. Read More

2. Novel Therapeutics, Biomarkers, and Mechanisms

• Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps

This study shows that chemotherapy can inadvertently reactivate dormant breast cancer cells, leading to metastatic relapse. Using a dormancy-tracing system, the authors reveal that chemotherapy-induced fibroblast senescence promotes NET formation, which remodels the extracellular matrix and awakens dormant cells. Combining senolytic drugs with chemotherapy prevents this reactivation, suggesting a strategy to reduce metastasis risk. Read More

• Microbial riboflavin inhibits ceramide synthase 3 to lower ceramide (d18:1/26:0) and delay colorectal cancer progression

This study reveals that elevated levels of ceramide d18:1/26:0 (C26), driven by increased CERS3 activity, promote colorectal cancer (CRC) progression by activating EGFR signaling. Tumor heterogeneity is influenced by gut bacteria like Bacteroides cellulosilyticus, which produce riboflavin that inhibits CERS3. Additionally, the FDA-approved drug aclidinium bromide shows potential in inhibiting CERS3, suggesting a novel therapeutic strategy for CRC. Read More

• Nerve-to-cancer transfer of mitochondria during cancer metastasis

This study reveals that neurons support breast cancer metastasis by transferring mitochondria to cancer cells, boosting their metabolic plasticity. Using denervation models and a new mitochondrial transfer tracker (MitoTRACER), researchers show that cancer cells receiving neuronal mitochondria have enhanced energy production and are more likely to metastasize, uncovering a novel nerve-cancer interaction. Read More

• Cancer-associated Fibroblast-like Cells Promote Osteosarcoma Metastasis by Upregulation of Phosphoserine Aminotransferase 1 and Activation of the mTOR/S6K Pathway

This study shows that cancer-associated fibroblasts (CAFs) promote osteosarcoma (OS) metastasis by upregulating the serine synthesis enzyme PSAT1 in OS cells. PSAT1 enhances migration via the PI3K/mTOR/S6K pathway. Inhibiting PSAT1 or mTOR signaling reduces OS metastasis, identifying them as potential therapeutic targets. Read More

• Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer

This study shows that HDAC3 drives resistance to AR-targeted therapy in mCRPC. The HDAC inhibitor vorinostat reduces tumor growth, partly by targeting HDAC3 and its interaction with the glucocorticoid receptor. These findings support HDAC inhibition as a strategy to overcome resistance in advanced prostate cancer. Read More

• PABPN1 as a pan-cancer biomarker: prognostic significance and association with tumor immune microenvironment

This study identifies PABPN1 as a potential pan-cancer biomarker for prognosis and immunotherapy. PABPN1 is overexpressed in many cancers and correlates with TMB, MSI, neoantigens, and immune cell infiltration, especially in urogenital cancers. Functional analysis and experiments confirm its involvement in immune regulation and tumor progression, supporting its role as a prognostic and immunological marker in cancer Read More

3. Cellular and Genetic Therapies (CAR-T, Gene Editing)

• Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in vivo CAR-T therapy for inflamm-aging

This study develops cardiolipin-inspired di-phosphoramide lipids (PL40) that enable efficient, ligand-free mRNA delivery to T cells in vivo. Using PL40 nanoparticles, researchers deliver mRNA encoding a CAR targeting uPAR, effectively treating liver fibrosis and rheumatoid arthritis in models. Humanized uPAR-CAR constructs show therapeutic potential for age-related inflammatory diseases. Read More

• Mesothelin is a surface antigen present on human meningioma and can be effectively targeted by CAR T-cells

This study highlights mesothelin as a viable target for CAR T-cell therapy in meningioma, a challenging CNS tumor with few options for aggressive forms. Mesothelin expression was confirmed in tumor tissues, and mesothelin-directed CAR T-cells showed potent anti-tumor activity in vitro, ex vivo, and in mouse models, leading to reduced tumor burden and extended survival. These findings provide a strong rationale for clinical development of mesothelin CAR T-cell therapy in treatment-resistant meningioma. Read More

• Targeted in vivo delivery of genetic medicines utilizing an engineered lentiviral vector platform results in CAR T and NK cell generation

This study introduces INT2104, a novel in vivo gene therapy platform using a lentiviral vector with a detargeted fusogen and CD7-targeting scFv to generate CAR20-expressing T and NK cells without preconditioning. In preclinical models, INT2104 produced functional CAR T and NK cells that depleted CD20+ B cells after one IV dose. This approach offers a more accessible, off-the-shelf alternative to traditional CAR T therapies. Read More

• Functional assessment of all ATM SNVs using prime editing and deep learning

This study functionally evaluated all 27,513 possible single-nucleotide variants (SNVs) in the cancer-associated gene ATM. Using prime editing and fitness assays with the drug olaparib, researchers assessed the effects of 23,092 SNVs and identified critical residues linked to cancer risk and prognosis. The remaining 4,421 SNVs were accurately predicted using a deep learning model, DeepATM. This comprehensive analysis enhances variant interpretation and supports precision oncology by addressing variants of uncertain significance (VUSs). Read More

4. Neurology, Neurodegeneration, and Psychiatry

• Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications

This study identifies two disrupted signaling pathways—Serpine2–Lrp1 and CD39–A3AR—in vascular dementia (VaD). Targeting these pathways enhances repair and function in a VaD model, revealing potential therapeutic strategies for this currently untreatable white matter disease. Read More

• Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading

This study reveals that depression accelerates Alzheimer’s disease (AD) progression by enhancing Aβ plaque deposition and cognitive decline in AD mice. The mechanism involves increased microglial lactate, which activates the Kv1.3 potassium channel, promoting the spread of Aβ-containing exosomes. Importantly, microglia-specific Kv1.3 knockout reverses these effects, identifying Kv1.3 as a potential therapeutic target in depression-exacerbated AD pathology. Read More

• Excitatory-neuron-derived interleukin-34 supports cortical developmental microglia function

This study identifies interleukin-34 (IL-34), produced by excitatory neurons, as a crucial regulator of microglial maturation and function during early postnatal brain development. IL-34 maintains healthy microglia and prevents excessive synaptic pruning in the anterior cingulate cortex. Loss or blockade of IL-34 leads to reduced microglial markers and increased aberrant synapse engulfment, highlighting its role in neuron-microglia communication. Read More

• Mild Chronic Colitis Exacerbates Intracerebral Inflammation in Mice with Parkinson's Disease Through LRRK2-Mediated Regulation of NF-κB Activation and Inhibition of Nrf2

This study shows that LRRK2 links gut inflammation to Parkinson’s disease by promoting NF-κB–mediated inflammation and suppressing Nrf2 signaling. In a dual-hit mouse model, elevated LRRK2 in both the colon and brain was associated with barrier disruption, neuroinflammation, and neuron loss, highlighting its role in gut-brain inflammatory crosstalk in PD. Read More

• Cryptic Splicing of GAP43 mRNA is a Novel Hallmark of TDP-43-Associated ALS and AD

This study reveals that TDP-43 directly regulates GAP43 expression by binding to its pre-mRNA. In ALS and Alzheimer's disease, TDP-43 dysfunction leads to inclusion of a cryptic exon (4a1), reducing GAP43 protein and impairing axonal regeneration. GAP43 loss contributes to neurodegeneration, and exon 4a1 inclusion may serve as a marker of TDP-43-related pathology. Read More

5. Cardiology and Metabolic Disease

• SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway

This study shows that SESN2 overexpression disrupts exosome-mediated damage spread in diabetic kidney disease by inhibiting Rab7a ubiquitination and enhancing MVB degradation and lysosomal function, making SESN2 a potential therapeutic target. Read More

• Huotan Jiedu Tongluo Decoction targets Nrf2-mediated macrophage autophagy to inhibit ferroptosis and reduce atherosclerotic lesions

This study shows that HTJDTLD, a traditional Chinese medicine, combats atherosclerosis by activating the Nrf2/autophagy pathway to inhibit ferroptosis in macrophages. It improves lipid metabolism, reduces inflammation and oxidative stress, and its effects depend on Nrf2, highlighting its therapeutic potential for atherosclerosis. Read More

• Optogenetic vagal nerve stimulation attenuates heart failure by limiting the generation of monocyte-derived inflammatory CCRL2+ macrophages

This study shows that vagal nerve stimulation (VNS) protects against heart failure by reducing pro-fibrotic Ccrl2⁺ macrophages through α7nAChR activation and NRF2 upregulation, highlighting the vagal neuroimmune axis as a potential therapeutic target. Read More

• Naringenin exerts antiarrhythmic action in septic cardiomyopathy by downregulating the CaMKⅡ/Drp1/Bcl-2 pathway

This study shows that naringenin, a natural flavonoid, protects against septic cardiomyopathy (SCM) by reducing inflammation, improving cardiac function, and decreasing arrhythmia risk. It works by targeting the CaMKII/Drp1/Bcl-2 pathway, improving mitochondrial function and reducing cell death. These findings highlight naringenin’s potential as a treatment for SCM-related heart dysfunction. Read More

• E3 Ubiquitin Ligase TRIM16-Mediated K63-linked Ubiquitination of DAB2 Enhances Integrin β1 Endocytosis to Facilitate Vascular Calcification

This study identifies TRIM16 as a key driver of vascular calcification in CKD. TRIM16 promotes K63-linked ubiquitination of DAB2, triggering integrin β1 endocytosis and FAK-STAT3 signaling, leading to vascular smooth muscle cell calcification. Blocking TRIM16 or DAB2 reduces calcification, highlighting the TRIM16-DAB2 pathway as a potential therapeutic target. Read More

6. Computational Medicine, AI, and Multi-Omics Analysis

• AI-enabled molecular phenotyping and prognostic predictions in lung cancer through multimodal clinical information integration

This study presents LUCID, a multimodal data integration framework for non-invasive prediction of EGFR mutation status and survival outcomes in lung cancer patients. By combining CT images, clinical complaints, lab tests, and demographics, LUCID achieved high accuracy (AUCs 0.851–0.881 for mutation, 0.821–0.912 for survival) in a 5,175-patient cohort and remained robust across external validations and incomplete data scenarios. Read More

• Machine learning and the nomogram as the accurate tools for predicting postoperative malnutrition risk in esophageal cancer patients

This study developed and validated tools to predict malnutrition one month after esophageal cancer surgery. Among 1,693 patients, the Random Forest model had the best performance, while a nomogram using five clinical factors (gender, age, BMI, neoadjuvant therapy, and sarcopenia) offered similar accuracy and greater clinical usability. Both tools effectively identified patients at high risk, supporting early intervention. Read More

• Identification and validation of NETs-related biomarkers in active tuberculosis through bioinformatics analysis and machine learning algorithms

This study identifies NETs-related genes—CD274, IRF1, and HPSE—as potential biomarkers to distinguish active TB (ATB) from latent TB infection (LTBI). These genes showed high diagnostic accuracy and strong links to neutrophil activity. Regulatory and drug-target analyses suggest therapeutic potential, with several candidate drugs identified. Further validation is needed to confirm their clinical utility. Read More

• Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer

This study reveals that polyamine metabolism is significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) and linked to poor prognosis. A polyamine metabolism-based score (PMscore) stratified patients by metabolic and immune profiles. NT5E (CD73) emerged as a key regulator, promoting tumor growth and immune evasion. Targeting NT5E and polyamine metabolism may offer a novel therapeutic strategy for PDAC. Read More

• An in silico evaluation of lorlatinib as a potential therapy for novel amino acid substitutions in the tyrosine kinase domain of the ALK protein associated with cancer

This study identifies 53 harmful ALK gene mutations across various cancers and evaluates lorlatinib, a third-generation ALK inhibitor, using in silico methods. Lorlatinib showed strong binding to all mutations, suggesting its potential to treat a broader range of ALK-positive tumors beyond lung cancer. The findings support lorlatinib as a promising targeted therapy and highlight the value of computational drug repurposing. Read More

Additional Highlights

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

• Senescent macrophages induce ferroptosis in skeletal muscle and accelerate osteoarthritis-related muscle atrophy

• AhR-mediated histone lactylation drives cellular senescence during benzo[a]pyrene-evoked chronic obstructive pulmonary disease

• Japan’s Ministry of Health, Labour and Welfare accepts regulatory application to expand use of GSK’s RSV vaccine, Arexvy, in adults aged 18-49 at increased risk of severe RSV disease

• Madrigal Receives Positive CHMP Opinion for Resmetirom (Rezdiffra™) for the Treatment of MASH with Moderate to Advanced Liver Fibrosis

• Sarclisa recommended for EU approval by the CHMP to treat transplant-eligible newly diagnosed multiple myeloma

• Linerixibat accepted for review by the European Medicines Agency for cholestatic pruritus in patients with primary biliary cholangitis (PBC).

• Biocon Biologics Receives Health Canada Approval for Yesafili™ (aflibercept); First Global Launch Scheduled for July 2025

• IMBRUVICA® (ibrutinib) receives positive CHMP opinion for the treatment of patients with previously untreated mantle cell lymphoma (MCL) who would be eligible for autologous stem cell transplant

• DARZALEX® (daratumumab) receives the first positive CHMP opinion for patients with high-risk smouldering multiple myeloma

• Johnson & Johnson Launches the PolyphonicTM AI Fund for Surgery to Advance Data-Driven Healthcare