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Glioblastoma (GBM) is an aggressive tumor characterized by an immunosuppressive microenvironment. Here, the authors present a therapeutic approach based on the implantation of a biodegradable scaffold for the sustained, local release of a TLR7/8 agonist at the time of tumor resection, to achieve anti-tumor immunity and protection from future tumor challenge.

LaccID, an engineered laccase, enables hydrogen-peroxide-free proximity labeling and electron microscopy (EM) in mammalian cells. Notably, LaccID is selectively active at the cell surface, enabling the mapping of the dynamic T cell–tumor surfaceome and its use as a genetically encodable EM tag, expanding the toolkit for cell-based imaging and proteomics.

Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

In this work, authors use cryo-EM and live-cell BRET assays to show that GPR3 can form constitutive dimers.

The Zika viral protease NS2B-NS3 is a crucial target for antiviral drug development due to its role in processing viral polyproteins. Here, the authors utilize crystallographic fragment screening and deep mutational scanning to identify binding sites for resistance-resilient inhibitors.

Debio 1453, a FabI inhibitor, shows potent activity against antibiotic-resistant Neisseria gonorrhoeae, rapidly killing bacteria in vitro and clearing infection in mice, supporting its potential for treating drug-resistant gonorrhoea.

Heart failure is a leading cause of morbidity and mortality, and ERBB4 signaling has been proposed as a potential therapeutic target. Here they identify small molecule ERBB4 agonists capable of decreasing cardiomyocyte damage and fibrosis in models of cardiovascular disease.

In a randomized, placebo-controlled, stepwise dose-escalation phase 1 trial evaluating a conjugate vaccine against both typhoid and invasive non-typhoidal Salmonella infections, the vaccine was found to be safe and immunogenic in healthy adults.

The developing heart integrates several progenitor cell types. Here they show that the pericardium enveloping the heart develops among cells that form the mesothelium around inner organs and body cavities, distinct from the classic heart field.

CAR-T cells have been found to be less effective as treatment for solid tumours. Here the authors, utilising B7H3 as an antigen, consider how changes in B7H3 binders lead to functional changes of CAR-T cells and differences in tumour outcomes in humanised mouse tumour models.

Presence of peritoneal metastasis is associated with a decreased survival in patients with colorectal cancer. Here, the authors show that peritoneal-resident macrophages promote the formation of an immunosuppressive environment that facilitate peritoneal metastasis in colorectal cancer.

Complexes of the transcription factor Ume6 bridge morphogenesis, adherence and hypoxic genes that determine biofilm architecture in the human fungal pathogen Candida albicans.

Spin-enhanced lateral flow tests use nanodiamonds for the sensitive, robust detection of disease biomarkers. Here, authors report a clinical evaluation of a test for SARS-CoV-2 antigen, finding 95.1% sensitivity (Ct ≤ 30) and 100% specificity, with detection 2.0 days earlier than conventional tests.

Molecular glues have great potential for drug discovery if they can be systematically discovered. Konstantinidou, et al describe a scaffold-hopping approach using multicomponent reaction chemistry to design molecular glues that induce 14-3- 3σ/ERα formation in cells.

STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

Pocock et al. reveal that transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor drives robust maturation of multicellular human cardiac organoids, enabling modeling of desmoplakin cardiomyopathy dysfunction, which could be rescued using the bromodomain and extra-terminal inhibitor INCB054329.

Drug resistance remains a major challenge in cancer treatment. Here, the authors identify Connexin43 as target that enhances BRAF/MEKi efficacy by interfering with DNA repair pathways, overcoming drug resistance. They develop an mRNA therapy that improves efficacy and sensitizes resistant cells.

The authors introduce the Neurolipid Atlas, a dynamic resource for the community to gain insight into lipid alterations in neurodegenerative disease, and they leverage the platform to show how cholesterol alterations in astrocytes can dysregulate neuroinflammatory pathways in Alzheimer disease.

This study reveals how the pathogen Staphylococcus aureus adapts to the lung microenvironment, rich in host metabolites fumarate and itaconate, by using a key enzyme, FumC, to support its metabolic fitness, survival, and persistence.

DNA replication stress is a driver of genome instability. Here, the authors identify a role of the E3 ligase RNF25 in promoting replication stress tolerance. Mechanistically, RNF25 recruits the fork protection factor REV7 to stalled replication forks and prevents nucleolytic degradation.

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants.

Light can control neural activity but often requires genetic modification. Here, the authors present a graphene-based platform for non-genetic light controlled neuronal stimulation, enabling all-optical network analysis, stem cell derived neuron maturation, and closed-loop robotics.

An NNMT inhibitor reduces tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing cancer-associated-fibroblast-mediated recruitment of myeloid-derived suppressor cells and reinvigorating CD8⁺ T cell activation.

Genome-scale genetic screens identify the small RNA-binding protein La as a strong mediator of prime editing.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

FIKK effector kinases underwent rapid evolutionary expansion and are a druggable target in Plasmodium falciparum.

The M₅ muscarinic acetylcholine receptor represents a promising therapeutic target for neurological disorders. Here, the authors reveal a 2.1 Å cryo-EM structure of the M₅ bound to a selective positive allosteric modulator site that enables structure-based drug design.

The native anaplastic lymphoma kinase (ALK) oncofetal protein is expressed in neuroblastoma and in multiple pediatric and adult solid tumors. Here, the authors show an ALK-directed antibody-drug conjugate with therapeutic efficacy in ALK-expressing preclinical models.

The actin methyltransferase SETD3, by virtue of its ability to interact with the viral 2A protein and independently of its enzymatic activity, is necessary for RNA replication of several enteroviruses in cell culture and in vivo.

As proof of principle, an analysis using a suite of human-aligned immunocompetent mouse models of hepatocellular carcinoma identifies a promising therapeutic candidate, cladribine, which acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.

RNF213 is an E3 ligase with ATPase activity. Here, the authors show that RNF213 is activated by ATP binding and senses cellular energy states, and reveal a transthiolation mechanism induced by immune signals through ATP increase in macrophages.

Mutations of the histone H3K36-specific methyltransferase ASH1L have been linked to several human diseases. Here, the authors report the mechanism by which three C-terminal domains in ASH1L regulate its enzymatic activity and interact with chromatin.

The class Frizzled of G protein-coupled receptors (GPCRs) consist of ten Frizzled (FZD_1-10) subtypes and Smoothened (SMO). Here the Schulte laboratory demonstrates that FZDs differ substantially from SMO in receptor activation-associated conformational changes, while SMO manifests a preference for a straight TM6, the TM6 of FZDs is kinked upon activation.

Microbes frequently encounter suboptimal conditions. Here, Shabestary et al. show that phenotypic heterogeneity is an important feature of Saccharomyces species adaptation where amino acid identity serves as an environmental cue driving this adaptive process.

NGPS is an accelerated aging condition, caused by a mutation in BAF. Here, we report the results of an unbiased, whole genome CRISPR microscopy screen aimed at restoring nuclear envelope integrity in NGPS patient cells.

Gut microbiota contribute to the pathogenesis of ulcerative colitis (UC), but the molecular mechanisms are still unclear. Here the authors show that colonic fluid from patients with UC is enriched for bacteria extracellular vesicles (BEV) coated with host IgA, and that these IgA-coated BEV may activate CD89⁺ immune cells to aggravate inflammation and colitis in mouse models.

Here the authors provide a comprehensive evaluation of important pre-analytical variables affecting extracellular RNA quantification and analysis in the exRNAQC study, examining eight RNA purification methods, ten blood collection tubes, and three time intervals for blood processing.

The molecular mechanisms of cell entry for the recently identified highly pathogenic feline coronavirus FCoV-23 are characterized in detail.

An atlas study of adipose tissue in people with obesity undergoing weight loss and their lean counterparts reveals that weight loss reduces cell senescence but cannot reverse all the metabolic problems caused by obesity.

Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, Zhao et al. explore the mechanisms driving pathogen’s adherence to skin, involving a conserved adhesin, as well as the potential of collagen coatings as a strategy to reduce C. auris adherence to abiotic surfaces.

Sexual forms of malaria parasites are responsible for transmission to the mosquito. Anti-malarial drug resistance remains a serious problem and requires advent of new drug therapies. Here, the authors present a high-throughput screen of potential antimalarial compounds, identifying seventeen drug-like molecules specifically targeting transmission.

A technique for the site-directed conjugation of antibodies via the small-protein ubiquitin allows for the efficient multivalent conjugation of antibodies and nanobodies to fusions of ubiquitin with molecular or proteinic moieties.

Root microorganisms can trigger the release of immune-stimulating N-hydroxypipecolic acid from Arabidopsis roots by manipulating a standby circuit of its continuous synthesis and immobilization. N-hydroxypipecolic acid thereby influences shoot growth and pathogen defence.

Protein/protein interaction (PPI) interfaces have emerged as drug targets to develop medications with less side effects. Here, Dvorak et al. show that small molecule targeting of PPIs in the brain is an approach for psychiatric drug discovery.

Dinoflagellates and cyanobacteria produce saxitoxin (STX) congeners that block voltage-gated sodium channels. Here authors show how amphibians may sequester STX congeners using a ‘lock and key’ mode, expanding the understanding of toxic sponge action.

Construction and analysis of 2,901 promoter–GFP fusions in Salmonella reveal dynamic, heterogeneous transcriptional activity, including roles for manganese homeostasis and Entner–Doudoroff carbon metabolism in promoting intramacrophage growth and survival of bacteria.