Olga Payar @Olgapaval

Mechanobiology meets synthetic immunotherapy. A new Nature Biomedical Engineering study uncovers how mechanical softness creates a stem-like, CAR-T-resistant tumor population—and rewires it into a therapeutic vulnerability. Key findings 🧬 Soft ECM promotes CAR-T resistance Across breast cancer and glioblastoma models, tumor cells cultured on soft extracellular matrix (ECM) were significantly less susceptible to CAR-T-mediated killing despite unchanged target antigen expression. ⚡ Softness triggers an exATP–Ca²⁺ signaling program Soft ECM increased: • extracellular ATP (exATP) • sustained intracellular calcium activity Blocking calcium signaling restored CAR-T cytotoxicity, identifying the exATP/Ca²⁺ axis as a mechanistic driver of immune resistance. 🎥 A genetic "mechano-recorder" captures mechanical history The authors engineered a doxycycline-gated calcium-responsive transcriptional recorder that permanently labels cells experiencing sustained softness-induced calcium signaling. Unlike GCaMP, which reports only instantaneous calcium flux, this recorder stores prior mechanosensing history as a stable fluorescent output for downstream sorting and transcriptomic profiling. 🌱 Softness-induced cells acquire a stem-like program Recorder-positive cells displayed features of cancer stem-like cells (CSLCs), including: • EMT activation • hypoxia signatures • KRAS signaling • CD44↑ / ALDH1↑ / CD24↓ • increased mammosphere formation • softer biomechanics • greater resistance to CAR-T killing Importantly, similar mechanostemness signatures were validated in patient-derived triple-negative breast cancer samples and additional solid tumor models. 🔄 Reprogramming resistance into a target The fluorescent reporter was replaced with CD19, generating a synthetic mechano-reprogrammer. Softness-responsive cancer stem-like cells now expressed CD19, enabling elimination by clinically established CD19 CAR-T cells. This strategy: ✅ restored killing of soft tumor cells in vitro ✅ enhanced CAR-T activation programs ✅ increased T-cell infiltration ✅ improved tumor control in xenograft models when combined with EGFR-CAR-T cells. Why this matters Rather than attempting to eliminate mechanical heterogeneity, this work leverages mechanobiology as an input signal. Mechanical softness becomes an exploitable biomarker that identifies immune-evasive cancer stem-like cells and converts them into CAR-T targets through synthetic gene circuitry. This introduces a new therapeutic concept: Mechanosensing → Cellular recording → Genetic rewiring → Precision immunotherapy It represents one of the first demonstrations that tumor biomechanics can be computationally encoded into programmable therapeutic logic, potentially opening a new direction for solid tumor CAR-T engineering. Citation Qu Y. et al. Identifying and reprogramming softness-driven cancer stem-like cells overcomes CAR-T cell resistance in solid tumours. Nature Biomedical Engineering (2026). DOI: 10.1038/s41551-026-01722-7

Data identify NOP16 as a previously unrecognized modulator of class switch recombination, highlighting its relevance in adaptive immunity and extending its functional significance beyond cancer biology. Learn more in The JI: ow.ly/thQ450ZhTji.

Regulation of solid tumors by the peripheral nervous system Journal of Experimental Medicine (2026) DOI: 10.1084/jem.20251333 The nervous system is no longer viewed as a passive bystander in cancer—it is now recognized as a master regulator of the tumor microenvironment. This comprehensive JEM review synthesizes the rapidly expanding field of cancer neuroscience, describing how sympathetic, sensory, and parasympathetic nerves orchestrate tumor growth, metastasis, immune evasion, metabolism, and therapeutic resistance. Key insights 🧠 Peripheral nerves are integral components of the tumor ecosystem Rather than acting only on cancer cells, neural circuits coordinate communication among: • tumor cells • immune cells • endothelial cells • fibroblasts This positions the peripheral nervous system as an upstream regulator linking stress, inflammation, metabolism, and therapy-induced signals to cancer progression. ⚡ Neural signaling promotes invasion and metastasis Major neurotransmitters include: • Sympathetic → norepinephrine → β-adrenergic receptors • Sensory → Substance P (NK1R) and CGRP (CLR/RAMP1) • Parasympathetic → acetylcholine → muscarinic/nicotinic receptors These pathways activate invasion, cytoskeletal remodeling, angiogenesis, extracellular matrix remodeling, and immune suppression. 🔥 Tumor metabolism is directly supported by nerves Recent discoveries reveal neurons provide metabolic support by: • transferring functional mitochondria into tumor cells • supplying serine during nutrient deprivation • rewiring tumor bioenergetics • enhancing oxidative metabolism and metastatic capacity Neurons therefore function as metabolic partners—not merely signaling cells. 🛡️ Neural regulation suppresses anti-tumor immunity Adrenergic signaling promotes: • M2 macrophage polarization • dendritic cell dysfunction • CD8⁺ T-cell exhaustion • impaired antigen presentation Meanwhile sensory CGRP signaling further drives T-cell exhaustion, creating a profoundly immunosuppressive tumor microenvironment. 🌱 Tumors actively recruit and remodel nerves Cancer cells stimulate axonogenesis through: • NGF • BDNF • Netrin-1 • extracellular vesicles carrying axon-guidance molecules Stress and chemotherapy further amplify neurotrophin production, generating a feed-forward loop that increases tumor innervation and neural control of disease. 💊 Cancer neuroscience is becoming therapeutically actionable Several approved drugs already target neural pathways implicated in cancer: • β-blockers (propranolol, carvedilol) • NK1 receptor antagonists (aprepitant) • CGRP inhibitors • Trk inhibitors • Botulinum toxin • Neuromodulation approaches Emerging clinical data suggest β-blockers may reduce metastasis and improve outcomes—particularly in triple-negative breast cancer—while aprepitant has been associated with reduced breast cancer mortality in observational studies. Why this matters Cancer should increasingly be viewed as a neuro-immune-metabolic disease, where neural circuits integrate psychosocial stress, nutrient availability, inflammation, and treatment-induced signals to coordinate multicellular tumor behavior. Targeting the nervous system offers a new therapeutic axis that complements immunotherapy and precision oncology, with the added advantage that several candidate interventions are already clinically available through drug repurposing.

Foxs1 defines a druggable CAF lineage switch. A new EMBO Molecular Medicine study identifies CD34⁺PI16⁺ fibroblasts as progenitors that differentiate into α-SMA⁺ myofibroblastic CAFs (myCAFs) through the transcription factor Foxs1, promoting tumor progression. Using lineage tracing, scRNA-seq, and spatial transcriptomics, the authors demonstrate that blocking this differentiation program suppresses tumor growth in melanoma and gastric cancer models. Key findings 🔹 CAF developmental trajectory revealed CD34⁺PI16⁺ fibroblasts represent an early progenitor CAF state. Pseudotime analysis places these cells upstream of ACTA2/α-SMA⁺ myCAFs, establishing a lineage relationship rather than separate CAF populations. 🔹 Foxs1 is the master regulator Foxs1 expression rises before α-SMA induction. FOXS1 directly binds the ACTA2 promoter, driving myCAF differentiation. Foxs1 knockdown preserves CD34/PI16 expression, suppresses α-SMA induction, and markedly reduces tumor growth in vivo. 🔹 Lineage ablation validates function Selective depletion of CD34⁺PI16⁺ fibroblasts significantly decreases tumor size. Loss of this lineage reduces myCAF formation without dramatically altering vessel density, suggesting CAF differentiation—not angiogenesis—is the dominant mechanism. 🔹 Spatial origin In situ sequencing localizes CD34⁺PI16⁺ fibroblasts near blood vessels, suggesting vascular adventitial fibroblasts as an important source of tumor CAFs. 🔹 Drug repurposing identifies CAF-state inhibitors Connectivity mapping (CMap/LINCS) identified compounds capable of maintaining the progenitor CAF state: Disulfiram WH-4-023 Monensin Penfluridol These compounds suppress Foxs1 expression, reduce α-SMA induction, preserve CD34⁺PI16⁺ fibroblasts, and inhibit tumor growth across preclinical models. Why this matters Rather than eliminating CAFs indiscriminately—a strategy that has largely failed clinically—this work suggests blocking a pathological fibroblast state transition. The concept resembles differentiation therapy: maintaining fibroblasts in a less tumor-supportive progenitor state instead of allowing conversion into contractile, tumor-promoting myCAFs. Research implications Identifies FOXS1 as a therapeutic target for CAF reprogramming. Demonstrates a scalable pipeline combining single-cell atlases + lineage tracing + spatial transcriptomics + CMap drug repurposing. Provides a framework applicable to fibrosis, stromal remodeling, and other diseases involving fibroblast state transitions. Citation Yang J, Chen T, Zhang R, et al. Foxs1-mediated transformation of CD34⁺ fibroblast to myCAFs promotes tumor growth. EMBO Molecular Medicine (2026). DOI: 10.1038/s44321-026-00476-8

In this month’s special issue on immune memory, a Review traces historical developments in #Tcell memory and discusses how new technologies have refined strategies for #vaccines and immunotherapies. @sjturn scim.ag/4p1jXqo

ROS is a double-edged sword in cancer. A comprehensive Journal of Advanced Research review highlights how moderate ROS fuels tumor initiation, metastasis, immune evasion, and therapy resistance, while excessive ROS overwhelms antioxidant defenses to induce apoptosis, ferroptosis, and other cancer cell death programs. Key insights: 🧬 ROS promotes cancer by activating NF-κB, PI3K/AKT, HIF-1α, remodeling the tumor microenvironment, and suppressing antitumor immunity. ⚔️ Cancer cells adapt through the NRF2–KEAP1, GPX4–GSH, and thioredoxin antioxidant systems, creating therapeutic vulnerabilities that can be exploited. 💊 ROS modulation enhances multiple treatment modalities: • Ferroptosis induction (GPX4 inhibition) • Radiotherapy & chemotherapy • Photodynamic/sonodynamic therapy • Overcoming TKI resistance by disrupting redox adaptation 🧪 An emerging concept is precision redox medicine—using mitochondrial redox signatures and digital biomarkers to stratify patients and tailor ROS-targeted interventions rather than applying uniform antioxidant or pro-oxidant strategies. 📈 Future directions include: • Tumor-specific ROS modulation • Combination therapies with immunotherapy • Targeting NRF2-dependent resistance • Mitochondrial biosensors for personalized treatment selection Rather than simply "reducing oxidative stress," the future of oncology may lie in precisely controlling where, when, and how much ROS is generated to selectively eliminate cancer while sparing normal tissue. 📄 ROS as a powerful instrument for the advanced cancer prevention and management: Facts and outlook Journal of Advanced Research (2026) DOI: 10.1016/j.jare.2026.07.002

🏥While immune checkpoint inhibitors have revolutionized small cell lung carcinoma (SCLC) management, clinical benefits remain restricted to a subset of patients. This study investigates baseline biomarkers for predicting outcomes in unresectable SCLC patients receiving first-line chemoimmunotherapy with or without radiotherapy. 👉doi.org/10.1007/s11684… #Prognosticutility

Did you know there are 4 distinct subtypes of #SmallCellLungCancer (SCLC)? Researchers are uncovering how these differences may help guide future treatments & clinical trial opportunities. Learn more about what this could mean for people living w/ SCLC: go2.org/blog/subtyping…

#Multiomics profiling of #SCLC reveals distinct intrinsic & extrinsic molecular signatures, characterized by intratumoral heterogeneity & recurrent oncogenic FAK splicing variants that predict poor prognosis and represent potential #TherapeuticTargets. #STTT #OpenAccess: doi.org/10.1038/s41392…

Can tumors silence innate immunity using their own metabolic waste? A new Immunity study reveals that lactate is not merely a metabolic byproduct—it directly binds the innate immune sensor STING, preventing cGAMP activation and enabling tumor immune evasion. Key findings 🧬 Lactate is a direct endogenous STING inhibitor Instead of acting only through acidification or lactylation, lactate physically binds the cGAMP-binding domain of STING (KD ≈ 32.7 μM), competitively blocking cGAMP binding, STING oligomerization, TBK1 activation, IRF3 phosphorylation, and type I interferon production. ⚡ EGFR rewires metabolism to suppress immunity EGFR activation recruits PKM2, which phosphorylates LDHA at Ser161, increasing LDHA activity and lactate production. EGFR → PKM2 → LDHA(S161) → Lactate ↑ → STING inhibition → Immune evasion 🔬 A new moonlighting role for PKM2 Beyond glycolysis, PKM2 functions as a protein kinase, phosphorylating LDHA to stabilize NADH binding and enhance enzymatic activity, thereby amplifying aerobic glycolysis and immunosuppression. 🛡️ Blocking PKM2 restores antitumor immunity Pharmacologic PKM2 inhibition: • Reduced lactate production • Reactivated STING signaling • Increased CD8⁺ T-cell infiltration • Suppressed glioblastoma growth • Synergized with anti-PD-1 immunotherapy in vivo 👨‍⚕️ Clinical relevance Human glioblastoma specimens with high LDHA Ser161 phosphorylation exhibited: • Lower STING activation • Reduced CD8⁺ T-cell infiltration • Poorer patient survival This identifies LDHA pS161 as a potential biomarker of immune suppression and therapeutic response. Why this matters This study fundamentally expands the role of lactate. Rather than serving only as a metabolic endpoint or signaling metabolite, lactate functions as an endogenous ligand for STING, directly coupling the Warburg effect to innate immune suppression. The findings also establish the EGFR–PKM2–LDHA–lactate–STING axis as a promising therapeutic target, suggesting that combining metabolic intervention with immune checkpoint blockade may overcome resistance in glycolytic tumors. Title: Lactate binds and inhibits the innate immune sensor STING to promote tumor immune evasion Journal: Immunity (2026) DOI: 10.1016/j.immuni.2026.06.004

@JTCancerCenter opening first-in-human trial of ML261, a potency-enhanced anti-DLL3 CAR T therapy, in relapsed SCLC and NEC. Advancing cellular therapies in solids. @ADesaiMD @salmanpunekar #LCSM #SCLC sprou.tt/1MBEdt2E1rS

SCAPeSCLC is now published in @Data_MDPI. Data Descriptor: doi.org/10.3390/data11… #SpatialTranscriptomics #LungCancer #SCLC #ComputationalBiology #Bayesian #DataScience

15 Mitochondrial Axes Every Aging, Sarcopenia & Heart Failure Researcher Should Measure Mitochondria are no longer viewed simply as cellular powerhouses. Across aging, sarcopenia, obesity, metabolic disease, and heart failure, they function as dynamic signaling hubs integrating bioenergetics, quality control, inflammation, and stress adaptation. Rather than relying on a single assay, a multidimensional mitochondrial profiling strategy is becoming the new standard. A practical framework includes 15 interconnected axes: • Oxidative phosphorylation (OCR, ATP production) • Mitochondrial biogenesis (PGC-1α–NRF1/TFAM) • Mitophagy (PINK1–Parkin, BNIP3/NIX, FUNDC1) • Fusion–fission dynamics (DRP1, MFN1/2, OPA1) • TCA cycle metabolic flux (^13C tracing) • Fatty acid oxidation (CPT1, acylcarnitines) • Membrane potential (ΔΨm) • Mitochondrial ROS • NAD+ metabolism (NAMPT–SIRT axis) • Cellular redox balance (GSH/GSSG) • Calcium handling and mPTP • mtDNA integrity and cGAS–STING activation • Mitochondrial proteostasis (ATF5, CLPP, LONP1) • Mitochondria–ER contact sites (MAMs) • Cardiolipin remodeling and mitochondrial peptides (MOTS-c, Humanin) For small pilot studies, signal-to-noise ratio matters more than assay quantity. A robust core panel can often be achieved using: ✅ Seahorse XF OCR ✅ TMRM membrane potential ✅ ATP/ADP ratio ✅ Citrate synthase activity ✅ mtDNA copy number ✅ mito-Keima mitophagy reporter ✅ TOM20 network morphology ✅ NAD+/NADH quantification ✅ Acylcarnitine metabolomics ✅ ^13C metabolic flux analysis Several methodological updates are also worth noting. Mdivi-1 is no longer considered a highly specific DRP1 inhibitor because of significant off-target effects. Likewise, high-dose etomoxir can inhibit mitochondrial respiration independently of CPT1, making low-dose treatment or genetic perturbation preferable. In mammalian systems, ATF5—not ATFS-1—is regarded as the principal regulator of the mitochondrial unfolded protein response (UPRmt). As the field shifts from descriptive mitochondrial biology toward mechanism-driven therapeutics, integrated mitochondrial phenotyping is becoming essential for identifying actionable pathways and biomarkers across aging-related diseases. #Mitochondria #Aging #Sarcopenia #HeartFailure #Metabolism #HFpEF #Mitophagy #Bioenergetics #Seahorse #Metabolomics Representative references (not a single source): Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011. DOI: 10.1038/nrm3028 Pickles S, Vigié P, Youle RJ. Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance. Curr Biol. 2018. DOI: 10.1016/j.cub.2018.01.004 Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol. 2018. DOI: 10.1038/s41556-018-0124-1 Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009. DOI: 10.1042/BJ20081386 Chandel NS. Evolution of Mitochondria as Signaling Organelles. Cell Metab. 2015. DOI: 10.1016/j.cmet.2015.05.013

A new Science #Immunology study shows that PD-L1 blockade can inhibit MHC-I presentation on tumor cells, enabling immune evasion and #metastasis in mouse models of #pancreatic cancer. @IngunnStromnes scim.ag/4eZ6JHb

ATP synthase isn't just making ATP—it may physically organize mitochondrial metabolism. A fascinating new Nature Communications study uncovers an unexpected structural connection between ATP synthase (Complex V) and the TCA cycle, suggesting that mitochondrial energy production is coordinated through a previously unrecognized protein interaction network rather than isolated enzyme complexes. Using in-solution crosslinking mass spectrometry (XL-MS) together with quantitative proteomics, complexome profiling and BN-PAGE, the authors mapped protein interactions inside intact mouse heart mitochondria under physiological conditions and during mitochondrial dysfunction caused by LRPPRC deficiency. The most surprising discovery is that the F₁ catalytic head of ATP synthase extensively contacts multiple TCA-cycle enzymes, including citrate synthase, isocitrate dehydrogenases, α-ketoglutarate dehydrogenase, succinyl-CoA ligase, fumarase and malate dehydrogenase. Until now, Complex II was generally considered the only structural bridge between oxidative phosphorylation and the TCA cycle. These findings expand that paradigm by positioning ATP synthase itself as a central metabolic interaction hub. When mitochondrial gene expression was impaired through cardiac Lrpprc knockout, ATP synthase underwent profound structural remodeling. Loss of the mtDNA-encoded ATP6 destabilized the F₀ membrane sector, causing partial dissociation of the F₁ catalytic domain while preserving its catalytic activity. At the same time, interactions between the detached F₁ head and TCA-cycle enzymes nearly doubled, accompanied by increased associations with fatty-acid β-oxidation and ketone-body metabolism enzymes. Another key observation involves ATPase Inhibitory Factor 1 (ATIF1). Under normal conditions, ATIF1 predominantly exists in inactive oligomeric assemblies. During ATP synthase dysfunction, however, ATIF1 shifted into its active inhibitory conformation and bound directly to the F₁ catalytic head through its N-terminal inhibitory domain, effectively suppressing ATP hydrolysis and pushing mitochondria toward an energy-conserving state. The proposed model is compelling: respiratory-chain dysfunction destabilizes ATP synthase, partially releases the F₁ head, strengthens its association with central metabolic enzymes, and simultaneously recruits ATIF1 to prevent futile ATP consumption. Rather than passive structural damage, this appears to represent an adaptive mitochondrial remodeling program that coordinates bioenergetics with metabolic rewiring during energetic stress. Beyond revealing a new layer of mitochondrial organization, this work provides a mechanistic framework for understanding diseases involving mtDNA defects, ATP synthase instability, cardiomyopathy, and mitochondrial encephalomyopathies. It also highlights crosslinking mass spectrometry as a powerful approach for uncovering transient metabolic interaction networks that are invisible to conventional structural biology. #Mitochondria #ATPSynthase #Metabolism #TCACycle #Proteomics #CrosslinkingMS #CardiacMetabolism #OXPHOS #NatureCommunications

🔥A blood-brain barrier-like vascular gate (BVG) limits immunotherapy efficacy in neuroendocrine cancers 🆙 @CellCellPress ☑BVG restricts immune infiltration in SCLC 🎯ASCL1-IGFBP5-IGF1R axis drives BVG 🎯OSI-906 (IGF1Ri) enhances CD8+ T cell infiltration & synergizes with anti-PD1 🎙Dr. Yiyun Wang #LCSM @OncoAlert @Larvol cell.com/cell/fulltext/…

Impressive review in @Cancer_Cell from an impressive set of authors: Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts cell.com/cancer-cell/fu… @IamLinghua @HHuanglab @MaraShermanLab @shouval @BiffiGiulia

🆕New in #JEV🆕 Characterizing the Fate of Anti-CS1 Nanobody Displaying Extracellular Vesicles in Multiple Myeloma #extracellularvesicles #multiplemyeloma #nanobodies isevjournals.onlinelibrary.wiley.com/doi/epdf/10.10…

@Cell_Metabolism Y en exceso, el cáncer…

New! Online now: Methionine-supplemented longevity diet increases growth hormone, GLP-1, and FGF21; reduces frailty; and promotes healthspan dlvr.it/TT9s5M