Cancer-associated fibroblasts (CAFs) represent a major structural component of solid tumors and play crucial roles in cancer progression and drug resistance. However, their developmental origin, differentiation trajector...Cancer-associated fibroblasts (CAFs) represent a major structural component of solid tumors and play crucial roles in cancer progression and drug resistance. However, their developmental origin, differentiation trajectory, and therapeutic potential remain poorly defined. Using advanced approaches-including inducible genetic lineage tracing, single-cell RNA sequencing, and spatial transcriptomic profiling-we identified a population of Cd34Pi16 fibroblast progenitors (Cd34 CAFs) in both melanoma and gastric cancer. We delineated their differentiation trajectory toward Acta2 CAFs, driven by the upregulation of the transcription factor Foxs1. This work establishes the developmental origin of Acta2 CAFs and experimentally validates the Cd34 to Acta2 transition. By reverse-matching the transcriptional signatures of Acta2 CAF differentiation with the CMap/LINCS L1000 drug perturbation database, we identified four small-molecule candidates predicted to inhibit tumor-induced Foxs1 upregulation. These compounds effectively suppressed Cd34 CAF differentiation, maintaining the progenitor-like Cd34 state. Collectively, this study proposes a novel antitumor strategy that targets CAF lineage development to restrain tumor progression.
Brain metastases (BrM) affect up to 30% of patients with solid tumors, yet durable intracranial control remains rare, and the biological drivers of this poor prognosis are incompletely understood. Patient-derived resourc...Brain metastases (BrM) affect up to 30% of patients with solid tumors, yet durable intracranial control remains rare, and the biological drivers of this poor prognosis are incompletely understood. Patient-derived resources, such as clinical cohorts, biobanks, functional ex vivo models, and multi-omic platforms, are central to closing this gap, but their generation and integration face substantial logistical and technical hurdles. Drawing on the RISEbrain consortium's experience, this Perspective examines BrM-focused cohorts and biobanks, highlighting the underused potential of rapid autopsy programs to capture early metastatic seeding. We discuss patient-derived organotypic cultures and emerging organoid-based "avatar" systems as functional platforms for therapeutic profiling, alongside the complementary strengths of bulk and single-cell/-nucleus transcriptomics. We outline how spatial transcriptomics and proteomics are resolving the architecture of the BrM microenvironment, and assess liquid biopsy approaches, including emerging photonic biosensors, for non-invasive monitoring. Together, these resources form an interdependent toolkit whose coordinated deployment will advance early detection, prevention, and precision treatment of BrM.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant germinal center (GC) reactions and autoantibody production. Expansion of T follicular helper (T) cells is a hallmark of SLE tha...Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant germinal center (GC) reactions and autoantibody production. Expansion of T follicular helper (T) cells is a hallmark of SLE that contributes to disease progression. Accordingly, T cells represent a promising therapeutic target for SLE. Here, we repurposed obeticholic acid (OCA), an FDA-approved drug for primary biliary cholangitis, as a potential treatment for SLE. OCA selectively inhibited the differentiation of T cells both in vitro and in vivo by suppressing the transcription factor ETV5, thereby downregulating SPP1, a key ETV5 target that promotes the development of T cells. In lupus-prone mice, OCA treatment reduced T- and GC B-cell populations and alleviated lupus-like manifestations, including autoantibody production and tissue pathology. These findings highlight OCA as a promising immunomodulatory candidate for SLE, providing avenues for devising a therapeutic strategy targeting the T cell-GC axis in systemic autoimmunity.
Microglia contribute to detrimental neuroinflammation under pathological conditions and thereby drive the pathogenesis and development of various diseases of the central nervous system (CNS). Here, the deubiquitinating e...Microglia contribute to detrimental neuroinflammation under pathological conditions and thereby drive the pathogenesis and development of various diseases of the central nervous system (CNS). Here, the deubiquitinating enzyme OTUB1 is identified as a regulator of microglial activation and CNS inflammation. In mice, microglia-specific OTUB1 deletion significantly ameliorates ischemic brain injury by reducing the pro-inflammatory activation of microglia. OTUB1 enhances Toll-like receptor (TLR) signaling through stabilizing UBC13 and TAB2, leading to the increased induction of cytokines. Notably, OTUB1 reduces the proteasomal degradation of TAB2 by reducing its K48 ubiquitination in a catalytic activity-independent manner. Moreover, microglia-confined OTUB1 deficiency also alleviates lipopolysaccharide-induced sickness behavior and experimental autoimmune encephalomyelitis in mice due to decreased neuroinflammation. Pharmacological inhibition of OTUB1 significantly mitigated ischemic stroke injury in mice. These findings reveal an important role of OTUB1 in potentiating microglial activation and neuroinflammation, providing a proof-of-principle observation for targeting OTUB1 in the treatment of TLR-associated neuroinflammatory diseases.
Bruckisch EHW, de Melo Aragão M, Dos Santos Rohde T
… +4 more, Huber AK, de Oliveira Torres M, Schwarz G, Liebsch F
EMBO Mol Med
· 2026 Jun · PMID 42380307
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Epilepsy, a common neurological disorder is frequently linked to genetic variants in synaptic proteins. Here, we describe a de novo pathogenic missense variant in the gephyrin G-domain (G134R) identified in an individual...Epilepsy, a common neurological disorder is frequently linked to genetic variants in synaptic proteins. Here, we describe a de novo pathogenic missense variant in the gephyrin G-domain (G134R) identified in an individual with developmental delay, epileptic seizures, microcephaly, dysmorphic features and short stature. Functional analyses reveal that G134R disrupts higher-order oligomerization, leading to impaired liquid-liquid phase separation (LLPS) and synaptic clustering. Recombinant G134R-gephyrin variant forms lower oligomers and retains only 60% of its molybdenum cofactor (Moco) synthesis activity while binding to glycine receptor models is unaffected. In non-neuronal cells, G134R fails to oligomerize beyond dimers with Moco synthesis activity reduced to 5%. In neurons, G134R is unable to form synaptic clusters and exerts a dominant-negative effect on WT-gephyrin, severely disrupting inhibitory synapse formation. Our findings highlight a critical role for the G-domain in gephyrin self-assembly and LLPS, shifting the focus from the E-domain-centric view of gephyrin function and providing a novel molecular mechanism for epilepsy linked to G-domain mutations.
Gigan JP, Garcia-Gonzalez P, Pilotti A
… +19 more, Galliot L, Reynaud A, Ghaffar Y, Flores-Santibáñez F, Ghafoori S, Seillier E, Lavignolle-Heguy R, Barros D, Bret C, Fichaux S, Combes A, Bani A, Rua R, Gatti E, Nal-Rogier B, Rocchi S, Moreaux J, Pierre P, Argüello RJ
EMBO Mol Med
· 2026 Jun · PMID 42373888
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The unfolded protein response (UPR) is a stress-adaptation pathway and therapeutic target in cancer, yet its pro-survival versus pro-death outcome is difficult to predict because the three ER sensors, PERK, IRE1α, and AT...The unfolded protein response (UPR) is a stress-adaptation pathway and therapeutic target in cancer, yet its pro-survival versus pro-death outcome is difficult to predict because the three ER sensors, PERK, IRE1α, and ATF6, are highly interconnected. Transcriptomic analyses identified sensor-specific gene signatures associated with patient survival across malignancies, and indicated that low IRE1α activity (low XBP1 signature or higher expression of RIDD targets) correlates with improved outcome. We developed SNUPR (single nuclei analysis of the unfolded protein response), an accessible flow cytometry approach that profiles all three branches in nuclear suspensions. SNUPR reveals marked heterogeneity of UPR activation across cancer cell lines that cannot be inferred from sensor expression. This heterogeneity is derived from differences in the strength and duration of PERK-mediated translational inhibition, which gates downstream translation-dependent IRE1α and ATF6 transcriptional programs. Finally, in multiple myeloma, we show that bortezomib-tolerant cells depend on IRE1α activity for survival, linking UPR state to proteasome-inhibitor resistance and positioning SNUPR to guide branch-selective targeting.
da Silva Padilha M, Koyuncu S, Chabanis E
… +7 more, Ryazanov S, Leonov A, Vilchez D, Klein R, Giese A, Griesinger C, Dudanova I
EMBO Mol Med
· 2026 Jun · PMID 42362792
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Huntington's disease (HD) is a hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by severe neurodegenerati...Huntington's disease (HD) is a hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by severe neurodegeneration of the basal ganglia and neocortex. No cure is currently available, and new treatment options are urgently needed. Here, we show that the oligomer modifying molecule anle138b (INN: emrusolmin) improves multiple disease phenotypes in cell culture and in two mouse models of HD. Application of anle138b reduced mHTT aggregate formation and ameliorated neurotoxicity in primary neurons. Oral administration of anle138b delayed deposition of mHTT inclusions, reduced brain atrophy, mitigated neuroinflammation and transcriptional alterations, improved motor function and extended life span in HD mice. Downregulation of striatal markers and synapse loss in striatal spiny projection neurons were also partially rescued. No adverse effects of anle138b were observed in wildtype animals. Moreover, anle138b markedly decreased mHTT aggregation in human neural precursor cells differentiated from HD patient-derived induced pluripotent stem cells (iPSCs). Altogether these results illustrate the potential of anle138b as a disease-modifying treatment for HD.
EMBO Mol Med
· 2026 Jun · PMID 42321431
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Tumor vaccines represent a promising modality in cancer immunotherapy, but the limited immunogenicity of whole-tumor cell vaccines (WTCVs) restricts their clinical translation. Here, we developed a novel bacterialized tu...Tumor vaccines represent a promising modality in cancer immunotherapy, but the limited immunogenicity of whole-tumor cell vaccines (WTCVs) restricts their clinical translation. Here, we developed a novel bacterialized tumor cell (BTC) vaccine by coating amino-functionalized bacterial lysates onto the surface of tumor cells, a process we define as "bacterialization". In vitro and in vivo experiments demonstrated that BTCs efficiently promote dendritic cell (DC) phagocytosis, maturation, and antigen cross-presentation, enhance DC migration to draining lymph nodes (DLNs), and remodel the DLN microenvironment by expanding tumor-specific CD8⁺ T cells and memory CD8⁺ T cells, while reducing terminally exhausted CD8⁺ T cells. BTC vaccination elicited robust tumor-specific cellular and humoral immunity, which synergistically suppressed tumor growth and metastasis in five syngeneic murine tumor models with negligible adverse effects. Furthermore, BTC vaccination reversed the immunosuppressive tumor microenvironment by increasing functional CD8⁺ T cell infiltration and reducing inhibitory immune subsets, and exhibited significant synergistic anti-tumor effects when combined with anti-PD-1 immune therapy. These findings demonstrate that BTCs represent a safe and effective novel WTCV candidate with strong clinical translation potential.
Bishnu A, Zapata-Muñoz J, Taylor RW
… +2 more, Sakamoto K, Ganley IG
EMBO Mol Med
· 2026 Jun · PMID 42310391
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Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is t...Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. Here, we build on our work showing that AMPK can inhibit mitophagy via sequestration of the ULK1 autophagy-initiating kinase ULK1 and demonstrate that it is also critically relevant for mitophagy induced by FBXL4 disruption. Using FBXL4-deficient cells, as well as fibroblasts derived from MTDPS13 patients and a chemically-induced mouse model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers functional mitochondrial content. This work therefore validates AMPK as a realistic target in treating MTDPS13.
Killian M, Shoffner-Beck SK, Damelang T
… +33 more, Selva KJ, Wong KE, Davis SK, Haycroft ER, Wines BD, Hogarth PM, Kent SJ, Grange L, Gramont B, Schein F, Munoz-Pons H, Guichard I, Gaultier JB, Berger AE, Haccourt A, Chanut B, Jospin F, Bocquet A, Bouillet L, Ruivard M, Jamilloux Y, Sève P, Durieu I, Reynaud Q, Lega JC, Servettaz A, Marotte H, Cathébras P, Harlé R, Ollier E, Paul S, Arnold KB, Chung AW
EMBO Mol Med
· 2026 Jun · PMID 42310390
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Sjögren's Syndrome (SjS) has historically been associated with classical anti-Ro60/SSA, Ro52/SSA and La/SSB, however they are lacking in one third of the patients, which induces delays in diagnosis, and their disease-con...Sjögren's Syndrome (SjS) has historically been associated with classical anti-Ro60/SSA, Ro52/SSA and La/SSB, however they are lacking in one third of the patients, which induces delays in diagnosis, and their disease-contributing role is debated. Here we have applied a SjS-tailored Systems Serology approach to a cohort of 58 SjS and 16 non-SjS sicca syndrome patients, and 40 healthy individuals, involving a multiplex assay measuring antibody isotype, subclass, Fc Receptor and complement engagement to 14 SjS-related autoantigens, an antibody-glycosylation profiling assay and a phagocytosis cell-based assay. Via a machine learning approach, we have identified unique autoantibody signatures, including classical and non-classical autoantigens-related features especially involving autoantigen-specific Fc Receptor binding, with apparent functional consequences. These findings provide interesting insights into the autoantibody responses in SjS, possibly paving the way for improved diagnostics, especially in difficult-to-diagnose patients (e.g., seronegative SjS and non-SjS sicca syndrome patients), and novel therapeutic options targeting autoantibody-specific Fc/Fc Receptor-related effector functions.
Kosasih T, Morishima T, Lee S
… +5 more, Yoon J, Wakahashi K, Kim P, Sada A, Takizawa H
EMBO Mol Med
· 2026 Jun · PMID 42304106
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Psoriasis is an inflammatory skin disease initiated by environmental triggers and driven by disruption of T cell cytokine network in the cutaneous milieu. The fact that complete resolution of disease by targeting the key...Psoriasis is an inflammatory skin disease initiated by environmental triggers and driven by disruption of T cell cytokine network in the cutaneous milieu. The fact that complete resolution of disease by targeting the key inflammatory cytokines remains challenging indicates a contribution of other immune cells to the pathogenesis. Here, we study the role of neutrophils in psoriasis, the first-line innate immune defender that is short-lived but mobile and infiltrative into various tissues. We found that upon psoriasis induction, skin-resident endothelial cells are activated to produce G-CSF which contributes to emergency granulopoiesis in bone marrow and cutaneous accumulation of inflammatory neutrophils. Depletion of neutrophils or blockage of psoriasis-driven granulopoiesis by respective neutralizing antibodies lead to the reduction of cutaneous neutrophil burden and mitigates psoriasis pathogenesis. This mechanism appears to be conserved in human psoriasis, confirmed by public RNA-seq database reanalysis. Our findings uncovered and detailed the pathological crosstalk between skin and BM in psoriatic inflammation, proposing a potential therapeutic approach targeting cross-organ communication.
Rumpret M, Lannergård J, Kristensen BM
… +8 more, Lynskey NN, Bowen C, Johnsson E, Nilsson OR, Norrby-Teglund A, Stålhammar-Carlemalm M, Lindahl G, McCarthy AJ
EMBO Mol Med
· 2026 Jun · PMID 42298213
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Vaccine candidates are typically identified through characterization of microbial surface antigens expressed under laboratory conditions. Here, we studied the major human pathogen Streptococcus pyogenes and showed that S...Vaccine candidates are typically identified through characterization of microbial surface antigens expressed under laboratory conditions. Here, we studied the major human pathogen Streptococcus pyogenes and showed that Slr, a lipoprotein encoded by all strains, is not detected on the bacterial surface during growth in broth but nevertheless is targeted by protective antibodies in vivo, as demonstrated by passive and active immunizations in a mouse model of invasive infection. The expression of Slr is governed by the zinc-controlled regulator AdcR, indicating that zinc depletion triggers surface expression of Slr in vivo. During infection in humans and mice, the antibody response to Slr is comparable to that elicited by the classical M protein and is, intriguingly, directed almost exclusively against a region with histidine triad (HT) motifs, an outcome that may represent a mechanism of immune escape. For vaccine development, these data focus interest on Slr and other microbial surface proteins selectively expressed in vivo.
Korbmacher F, Long RKM, Fleckenstein H
… +8 more, Poliński P, Crusius D, Piatti L, López-Gutiérrez B, Batzilla A, Trivedi V, Ebisuya M, Bernabeu M
EMBO Mol Med
· 2026 Jun · PMID 42288671
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The sequestration of the malaria parasite in the microvasculature is a major driver of severe malaria, but the human specificity of Plasmodium falciparum has challenged our understanding of this key pathogenic process. A...The sequestration of the malaria parasite in the microvasculature is a major driver of severe malaria, but the human specificity of Plasmodium falciparum has challenged our understanding of this key pathogenic process. Advances in induced pluripotent stem cell (iPSC) technologies offer unique opportunities to study parasite-host interactions in a well-defined environment. However, endothelial iPSC differentiation methods often result in cells with mixed epithelial identity. Here, we have generated an iPSC line with inducible and simultaneous expression of ETS transcription factors (ETV2, FLI1, ERG), resulting in cells with improved endothelial identity and strong barrier function (ETS-iBMEC). Parasite-infected red blood cells and neutrophils display high binding to ETS-iBMEC. Exposure to parasite products caused transcriptional changes in metabolic and splicing genes, and key endothelial barrier and angiogenic pathways. Our study confirms the role of the angiopoietin-Tie2 axis in parasite-mediated barrier disruption and highlights the importance of new pathways, including VEGF-Notch signalling. Our novel iPSC-based approach represents a new in vitro platform to study the pathogenesis of human vascular infections.
Türkal M, Maeder C, Correia de Sousa M
… +6 more, Fournier M, El-Harane S, Gjorgjieva M, Foti M, Maecher P, Delangre E
EMBO Mol Med
· 2026 Jun · PMID 42271090
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Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), initiated by the pathological lipid accumulation within hepatocytes, can progress towards Metabolic dysfunction-Associated SteatoHepatitis (MASH) characte...Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), initiated by the pathological lipid accumulation within hepatocytes, can progress towards Metabolic dysfunction-Associated SteatoHepatitis (MASH) characterized by inflammation and fibrosis. Hepatic fibrosis is the strongest predictor of liver-related mortality, yet effective antifibrotic therapies remain limited, calling for identification of new molecular targets. Our previous work identified S100A10 as a MASLD promoter, suggesting that its association with AnnexinA2 (ANXA2) within the S100A10-ANXA2 heterotetramer (A2t) might promote hepatic fibrosis. Here, we inhibited A2t using its inhibitor, A2ti-1, in human hepatic stellate cells (LX-2) and in human multilineage liver organoids (HLOs) modeling MASLD. In LX-2, A2ti-1 reduced α-SMA protein levels and expression of profibrotic genes, indicating direct suppression of stellate cell activation. In HLOs, A2ti-1 significantly reduced fibrosis by lowering α-SMA levels, collagen deposition, and profibrotic gene expression, without altering steatosis. Mechanistically, A2ti-1 inhibited hepatic stellate cell activation through a SMAD-independent mechanism involving reduced STAT3 phosphorylation. These findings identify the S100A10-ANXA2 tetramer as a new regulator of hepatic stellate cells activation and highlight its inhibition as a promising antifibrotic strategy in MASH.
Pei HZ, Li H, Xue H
… +12 more, Wang W, Zhang H, Fan Z, Bai X, Han F, Li Q, Zhao Y, Yu L, Jia X, Guo Y, Liu W, Sun L
EMBO Mol Med
· 2026 Jun · PMID 42271089
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B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy characterized by rapid proliferation of immature lymphoid cells. Despite treatment advancements, relapse remains a significant challenge...B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy characterized by rapid proliferation of immature lymphoid cells. Despite treatment advancements, relapse remains a significant challenge. Understanding the molecular mechanisms that drive B-ALL progression is essential for developing more effective treatments. Here, we show that extracellular cyclophilin A (eCypA) is elevated in patients with B-ALL via both autocrine and paracrine mechanisms. Moreover, eCypA administration exacerbated B-ALL progression in a mouse model. Mechanistically, eCypA binds to the melanocortin 2 receptor and activates the downstream cAMP-PKA-CREB signaling pathway. This activation upregulates CD44, FN1, and MMP9 to promote trans-endothelial migration of B-ALL cells and increases the expression of anti-apoptotic proteins, thereby inhibiting cell apoptosis. Antibodies against CypA modestly reduced leukemia burden and delayed disease progression in both NALM6 xenograft and patient-derived xenograft mouse models. Furthermore, single-cell transcriptomics suggests that anti-CypA treatment reduces the proportion of cells with multipotent progenitor features and is accompanied by decreased CREB pathway activation. Collectively, these findings indicate that eCypA contributes to the progression of B-ALL and may represent a potential therapeutic target.
Ma Y, Yi J, Zheng C
… +8 more, Yang J, Li J, Yu M, Qian X, Ren J, Wu X, Lu Y, Liu P
EMBO Mol Med
· 2026 Jun · PMID 42265368
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Recent advances in next-generation sequencing have revealed that long non-coding RNAs (lncRNAs) can encode functional micropeptides through small open reading frames (sORFs), altering the perception of the non-coding gen...Recent advances in next-generation sequencing have revealed that long non-coding RNAs (lncRNAs) can encode functional micropeptides through small open reading frames (sORFs), altering the perception of the non-coding genome. In this study, we identified a 48-amino acid micropeptide named PAMP (proline-associated micropeptide), encoded by the lncRNA PSMA3-AS1, as a novel tumor suppressor in lung adenocarcinoma (LUAD). PAMP is significantly downregulated in LUAD tissues and positively correlates with favorable prognosis. Functional assays demonstrated that PAMP inhibits LUAD cell proliferation in vitro and suppresses tumor growth in vivo. Mechanistically, PAMP directly interacts with PYCR1, a key enzyme in proline biosynthesis. Structural modeling and mutagenesis revealed that the PAMP-F16 and PYCR1-N123 residues are critical for the interaction, resulting in the inhibition of PYCR1 enzymatic activity and decreased proline accumulation. Notably, synthetic PAMP administration recapitulates these anti-tumor effects, effectively reducing intracellular proline levels and impairing tumor progression in cellular and animal models. Together, our findings uncover a previously uncharacterized lncRNA-encoded micropeptide that orchestrates proline metabolic reprogramming to restrain LUAD development, offering new opportunities for metabolic intervention in precision oncology.
Li Y, Huang D, Liu C
… +11 more, Zhou Z, Song Y, Yang D, Rui W, Yang Z, Yu L, Wang C, Zheng Z, Wang J, Fu YX, Lin X
EMBO Mol Med
· 2026 Jun · PMID 42260138
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Adoptive T-cell therapies engineered with T-cell receptors (TCRs) or TCR-like antibodies have shown considerable promise in cancer immunotherapy. However, identifying tumor antigen-specific TCR-like antibodies, particula...Adoptive T-cell therapies engineered with T-cell receptors (TCRs) or TCR-like antibodies have shown considerable promise in cancer immunotherapy. However, identifying tumor antigen-specific TCR-like antibodies, particularly against human leukocyte antigen-presented neoantigens, remains challenging. Here, we present a function-based, rather than affinity-based, antibody screening platform utilizing Synthetic T-cell receptor and Antigen Receptor (STAR)-T cell libraries. We found that antigen engagement in STAR-T cells triggers synchronous receptor endocytosis and T-cell activation, and we integrated these paired processes into an Endocytosis-Activation (E-A) functional readout for antibody screening. Applying E-A functional screening, we rapidly identified multiple nanobodies targeting the cell-surface antigen CD22 as well as the intracellular neoantigen P53. STAR-T cells engineered with these nanobodies mediated potent anti-tumor efficacy both in vitro and in vivo. Furthermore, this platform yielded nanobodies that can be directly reformatted into other therapeutic modalities, including chimeric antigen receptors and bispecific antibodies, while maintaining cytotoxic function. Overall, the E-A screening platform links antibody discovery directly to T-cell function, providing a robust approach for identifying therapeutic antibodies, especially neoantigen-specific nanobodies, for T cell-based cancer immunotherapy.
Wu Z, Tien NTN, Klabunde B
… +15 more, Aasmul-Olsen K, Offersen SM, Yen NTH, Muk T, Thysen AH, Brix S, Brustad N, Wang T, Stokholm J, Bønnelykke K, Brunse A, Long NP, Chawes B, Bæk O, Nguyen DN
EMBO Mol Med
· 2026 Jun · PMID 42260137
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Preterm infants are highly susceptible to infections that can lead to sepsis, yet therapies beyond antibiotics are limited. Nutrition and host energy metabolism are known as immune modulators, but how they interact to me...Preterm infants are highly susceptible to infections that can lead to sepsis, yet therapies beyond antibiotics are limited. Nutrition and host energy metabolism are known as immune modulators, but how they interact to mediate newborn host infection defense remains poorly understood. Here, we identify tricarboxylic acid (TCA) cycle metabolites as key modulators of early life infection outcomes. First, in a birth cohort of 700 children, elevated plasma TCA metabolite levels were associated with reduced infection burdens and systemic inflammation. Next, in a piglet neonatal sepsis model, sustained hepatic TCA cycle activity was associated with survival. These led us to explore clinically relevant nutritional strategies boosting TCA cycle activity. Substituting glucose in parenteral nutrition for galactose or glucogenic amino acids improved both pathogen clearance and preserved glucose homeostasis and prevented lethal sepsis. Mechanistically, these interventions promoted hepatic metabolic rewiring from glycolysis toward TCA-cycle-based oxidative phosphorylation, while mitigating excessive inflammation and organ injury. Our findings establish a clear connection between systemic energy metabolism and neonatal infection defense, suggesting clinically relevant strategies to improve outcomes in vulnerable newborns.