Olga Payar @Olgapaval

New! Online now: IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition dlvr.it/TSzBBY

New #JITC article: "Novel CAR T cell blend targeting PDPN and GD2 to overcome glioblastoma heterogeneity" jitc.bmj.com/content/14/6/e… @FulviaFerrazzi @H_Einsele

Ha salido la nueva guía 2026 del síndrome cardiovascular-renal-metabólico (CKM) y trae cosas interesantes. Os dejo lo que me parece más destacable, lo bueno y lo que no me cuadra tanto 🧵 @AHAScience @ACCinTouch @AmDiabetesAssn @ASNKidney Corazón, el riñón y el metabolismo no van por separado. Y es bueno ponerlo también sobre el papel. Lo que más me gusta: → Se estadifica el CKM (0 a 4), también en niños, para frenarlo a tiempo y hasta hacerlo retroceder. → La obesidad se trata como la raíz, no como un factor más de la lista. POR FIN. → iSGLT2 y GLP-1 como modificadores de enfermedad → Mirar siempre el riñón con FGe + cociente albúmina/creatinina. → Y meten los determinantes sociales en la ecuación. Sigo 👇

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Excited to share out latest work, out this week in @NatureGenet . In this study, we using CRISPR screens to explore how sensing inflammatory cytokines exposes new tumor-intrinsic dependencies. @broadinstitute @MGBResearchNews nature.com/articles/s4158…

Can we revisit immunotherapy after progression on first-line chemoimmunotherapy in ES-SCLC? 🤔 In this real-world study (n=151), ICI rechallenge was associated with: ✅ Higher ORR (26% vs 11.8%) ✅ Better disease control (75% vs 47.1%) ✅ Longer PFS2 (4.0 vs 2.4 months) ✅ Longer OS (9.4 vs 6.2 months) While prospective validation is still needed, these data suggest that selected patients who initially benefited from immunotherapy may still derive benefit from an ICI-based approach beyond progression @OncoAlert @StephenVLiu @GlopesMd @weoncologists @ManuelDomine @christine_lovly @OncoReporte @MedwatchKate @LungCancerEu

New #JITC article: "Systemic pre-conditioning favors effector over exhausted CD8 T-cell subsets following Sup2-IL33 armored CAR T-cell therapy" jitc.bmj.com/content/14/6/e… @SundrudL @GeiselMed

THIS IS THE BEST PAPER OF 2026 SO FAR, A MONUMENTAL BREAKTHROUGH, A REVOLUTION IN THE FIELD OF INFLAMMATORY CONDITIONS: Interleukin-10 Autoantibodies and HLA-DRB1*01:03 in Inflammatory Bowel Disease | New England Journal of Medicine nejm.org/doi/10.1056/NE…

Tissue tension fosters macrophage-driven lipid peroxidation-induced DNA damage dlvr.it/TSzVNC

Important new paper on pulmonary carcinoids. not in the least, it changes the name to carcinoid/neuroendocrine tumor @IASLC Congratulations to @natasharekhtman from @MSKCancerCenter @AnjaRodenMD @IASLC @JTOonline @yasushi_yatabe jto.org/article/S1556-…

⭐️Online now Iron level and ferroptosis impair antitumor efficacy of CAR-T cells. by Dongrui Wang, Yongxian Hu, Pengxu Qian, He Huang & colleagues nature.com/articles/s4301…

Cancer stem cells orchestrate immune evasion through extracellular vesicle-mediated non-canonical signaling pathways dlvr.it/TT0Hqm

New #JITC article: "IFN-γ PET imaging stratifies and predicts response to CD137 agonism in a syngeneic colorectal tumor model" jitc.bmj.com/content/14/6/e… @waynestate

Inflammatory cytokines induce new cancer dependencies @NatureGenet @broadinstitute @MangusoLab nature.com/articles/s4158…

⭐️Now online In a large cohort of patients with ICB-treated glioblastoma, Catherine J. Wu & colleagues show that baseline mesenchymal transcriptional state predicts therapy response, and transition to non-mesenchymal state results in acquired resistance. nature.com/articles/s4301…

Check out our latest review👏! We dive deep into how cDC1s orchestrate anti-tumor immunity through cross-presentation, immune networking, and spatial organization.

Journal of Experimental Medicine @JExpMed

2 days ago

Ward, Kar, Balan, and Bhardwaj @BhardwajLab review how conventional type 1 #DendriticCells (cDC1s) coordinate antitumor immunity through cross-presentation, immune cell networking, and spatial organization in tumors. hubs.la/Q04kVmqr0 #CancerFocus #Immunotherapy

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Bioelectric signaling as an emerging layer of macrophage communication dlvr.it/TSywZ6 #immunology

Spotlight @ImmunityCP Fibroblasts hold the key to TLS formation cell.com/immunity/fullt… cell.com/cancer-cell/fu… @Cancer_Cell

Machine Learning + Molecular Dynamics Reveal a Novel Flavonoid BCL-2 Inhibitor 🧬 Can AI discover the next-generation Venetoclax? A new study combined deep learning, virtual screening, molecular docking, and molecular dynamics simulations to identify novel flavonoid inhibitors targeting the anti-apoptotic protein BCL-2, a validated therapeutic target in chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and multiple myeloma (MM). Key findings ✅ Built a deep neural network (DNN)-based QSAR model from 843 BCL-2 bioactivity records ✅ Screened a library of 4,857 flavonoids ✅ Predicted 83 compounds with potential BCL-2 inhibitory activity ✅ Molecular docking identified 10 top candidates ✅ 200-ns replicated molecular dynamics simulations revealed Comp-7 (3'-Prenylrubranine) as the most stable binder to BCL-2 Why Comp-7 stood out Although Venetoclax remained the strongest binder by docking score (-9.9 kcal/mol), Comp-7 demonstrated remarkable stability during long-timescale simulations: 🔹 RMSD converged within ~20 ns and remained below 0.2 nm 🔹 Stable protein dynamics with RMSF, SASA, and radius of gyration profiles comparable to Venetoclax 🔹 Maintained persistent hydrophobic interactions with key BCL-2 residues including ASP38, ARG42, TRP79, GLY80, ALA84, and LEU136 🔹 Displayed favorable drug-likeness characteristics with fewer medicinal chemistry rule violations than Venetoclax Why this matters Resistance to Venetoclax remains a major challenge in AML, CLL, and MM. This study highlights an emerging AI-driven drug discovery pipeline: 🧠 Deep learning → Virtual screening → Molecular docking → Molecular dynamics The identified hit, 3'-Prenylrubranine (Comp-7), is a relatively unexplored natural flavonoid with no substantial prior bioactivity literature, making it an intriguing scaffold for future BCL-2 inhibitor development. Important caveat This is an in silico discovery study. No cellular, animal, or clinical validation has yet been reported. Experimental confirmation will be required to determine whether Comp-7 truly induces apoptosis and overcomes Venetoclax resistance in hematologic malignancies. 📖 Reference Tondar A, Bepari AK, Reza HM, et al. Machine learning and molecular simulations reveal a prenyl plant flavonoid as a potent Bcl-2 inhibitor in cancer therapy In Silico Pharmacology (2026) DOI: 10.1007/s40203-026-00662-z #AIforDrugDiscovery #BCL2 #Venetoclax #AML #CLL #MultipleMyeloma #CancerResearch #MachineLearning #MolecularDynamics #DrugDiscovery #Flavonoids #ComputationalBiology #Bioinformatics #PrecisionOncology

Arterial stiffness is usually framed as a mechanical consequence of aging, blood pressure, and metabolic stress. But this new Aging Cell study suggests another layer: the immune repertoire itself may encode an early trajectory of vascular aging. Using peripheral TCRβ repertoire sequencing from 563 adults without overt cardiovascular disease, the authors linked immune repertoire architecture to brachial-ankle pulse wave velocity (baPWV), a clinical marker of arterial stiffness. The surprising finding: high PWV was not associated with the classic immunosenescence pattern of narrowed TCR diversity and dominant memory clone expansion. Instead, individuals with elevated arterial stiffness showed a paradoxical increase in TCRβ diversity, driven by broad remodeling of many low-frequency clonotypes. This is important because classical immune aging is often CD8+ memory/MAIT-biased, with repertoire contraction. Here, the PWV-associated signature was largely CD4+ T cell–driven, and it did not overlap with canonical age-related RFUs. The authors call this process “vascular immune remodeling.” Single-cell mapping suggested that these PWV-associated clonotypes preferentially localize to a naive-like / early-differentiation CD4+ compartment, but functionally they do not look “healthy naive.” Instead, they show features of: • chronic immune activation • interferon-α / interferon-γ response • proliferative restraint • impaired cell-cycle and metabolic programs • possible dysfunction rather than immune vigor The model proposed is elegant: vascular aging may have at least two partially dissociable immune trajectories. One is classical chronological immune aging, enriched in CD8+/MAIT-related repertoire shifts. The other is a CD4+ T cell-centered inflammatory remodeling state associated with subclinical arterial stiffening. Clinically, this matters because TCR features were predictive. A machine-learning model using PWV-associated repertoire functional units classified high PWV with AUC 0.817 in the internal validation set. The study remains cross-sectional, so causality is not proven. CD4+ remodeling may drive vascular stiffness, or vascular dysfunction may reshape immune tone. But either way, this work expands vascular aging beyond smooth muscle, collagen, elastin, and blood pressure. Key takeaway: arterial stiffness may carry an immune fingerprint—broad, low-frequency, dysfunctional CD4+ T cell remodeling—potentially opening a path toward immune-based vascular risk stratification and intervention. #Aging #VascularAging #Immunology #CD4Tcells #TCRrepertoire #CardiovascularDisease #Inflammaging #PrecisionMedicine

Trained Immunity Meets CAR-M: A New Playbook Against SCLC Small-cell lung cancer (SCLC) remains one of the deadliest solid tumors, with limited therapeutic options and a 5-year survival rate near 6%. While DLL3-targeted therapies such as ADCs, BiTEs, and CAR-T cells have shown promise, durable responses remain challenging due to poor tumor infiltration, immune suppression, and antigen escape. A new study introduces a compelling alternative: DLL3-targeted CAR macrophages (CAR-Ms) enhanced through β-glucan-induced trained immunity. Key Innovation Researchers engineered macrophages expressing a DLL3-specific CAR consisting of: DLL3 scFv CD8 hinge/transmembrane domain CD3ζ signaling domain Unlike CAR-T cells, macrophages naturally infiltrate solid tumors, phagocytose malignant cells, present antigens, and remodel the tumor microenvironment. Major Findings 🧬 Potent DLL3-specific killing ~60% killing of DLL3-high H146 SCLC cells in vitro Strong phagocytosis of DLL3-positive targets Near-complete destruction of DLL3+ tumor spheroids within 96 hours Minimal activity against DLL3-negative cells 🫁 Robust in vivo efficacy In both immunodeficient and immunocompetent mouse models: Significant tumor growth suppression Reduced tumor burden Increased tumor apoptosis No detectable systemic toxicity Importantly, CAR-Ms accumulated efficiently within tumors and persisted longer than control macrophages. Tumor Microenvironment Reprogramming DLL3-CAR-Ms transformed an immunologically "cold" SCLC microenvironment into a more inflamed state by: ↑ CD80+ M1 macrophages ↓ CD206+ M2 macrophages ↑ CXCL9/CXCL10/CXCL11 ↑ IL-2 and IFN-γ ↑ Antigen presentation programs These changes enhanced recruitment and activation of cytotoxic T cells. Synergy with PD-L1 Blockade Although anti-PD-L1 alone produced modest effects, combining checkpoint inhibition with DLL3-CAR-Ms generated significantly greater tumor control. This suggests macrophage-directed cellular therapy may sensitize otherwise resistant SCLC tumors to immune checkpoint blockade. The Most Exciting Part: Trained CAR-Ms The authors introduced a β-glucan training protocol: 24-hour β-glucan exposure 6-day resting period Tumor rechallenge The result was a macrophage population with durable innate immune memory. Compared with conventional CAR-Ms, trained CAR-Ms exhibited: ✅ Enhanced phagocytosis ✅ Increased cytotoxicity ✅ Sustained multi-round tumor killing ✅ Stronger inflammatory signaling ✅ Higher IFN-I responses ✅ Greater antitumor activity in vivo Mechanistic Insight: Mitochondria Drive Memory Multi-omics analysis revealed profound metabolic rewiring: Increased oxidative phosphorylation (OXPHOS) Elevated ATP production Increased mitochondrial mass Enhanced mitochondrial ROS (mtROS) Blocking mtROS with Mito-TEMPO markedly reduced: Tumor killing TNF-α production IL-1β production indicating that mitochondrial fitness is a central driver of trained CAR-M function. Why This Matters This work represents: 🔹 First DLL3-targeted CAR-macrophage therapy for SCLC 🔹 First demonstration of trained immunity engineering in CAR-Ms 🔹 Evidence that metabolic-epigenetic programming can enhance cellular immunotherapy durability 🔹 A potential strategy to overcome limitations of CAR-T therapy in solid tumors If validated clinically, trained DLL3-CAR-Ms could emerge as a next-generation platform combining innate immune memory, tumor penetration, and microenvironment remodeling for refractory neuroendocrine cancers. Reference Ying H et al. Trained immunity-primed DLL3-targeted CAR macrophages for the eradication of small cell lung cancer. Journal of Advanced Research (2026). DOI: 10.1016/j.jare.2026.05.047.