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COX-2-mediated prostaglandin E2 (PGE2) release from dying cancer cells contributes to cytotoxic therapy resistance. Here the authors show that cytotoxic drugs induce PGE2 release only in cancer cells with basal COX-2 activity and that pharmacological COX-2 inhibition can boost the efficacy of the combination of chemotherapy and PD-1 blockade.

Abeysundara, Rasnitsyn, Fong et al. report that the presence of leptomeningeal metastatic tumour cells leads to the recruitment and remodelling of fibroblasts, which, in turn, facilitate the colonization and outgrowth of medulloblastoma cells in the leptomeninges.

Longitudinal data in electronic health records could be used to improve definitions of patient clusters and therefore inform precision medicine interventions. Here, the authors introduce VaDeSC-EHR, a machine learning model that uses patient longitudinal trajectories and time-to-event data to define clusters.

Ossenkoppele, Salvado et al. show that plasma p-tau217 and tau-PET predict cognitive decline equally well among cognitively unimpaired individuals. Their combined use further boosts prognostic accuracy. A sequential approach can enhance precision and efficiency of preclinical Alzheimer trials.

The inter-individual variation of the immune system broadly impacts pathophysiology. Here, the authors use the hybrid mouse diversity panel as a surrogate for human natural immune variation and derive a macrophages gene signature robustly correlating with susceptibility to macrophage-related disorders in humans.

Secondary and exploratory analyses of the phase 3 NRG GY018 trial show that, in patients with advanced or recurrent endometrial cancer, first-line treatment with pembrolizumab together with paclitaxel and carboplatin leads to prolonged progression-free survival, according to blinded independent central review.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Tan and colleagues conducted a single-cell multiomic analysis of T cell acute lymphoblastic leukemia and identified a treatment-resistant subpopulation of bone marrow progenitor-like blasts associated with poor outcomes.

ctDNA is a known poor prognostic factor for multiple cancer types, but variant-specificity is unknown. Here, the authors show variant-specific association of ctKRAS levels with survival in previously untreated metastatic pancreatic ductal adenocarcinoma patients in multiple cohorts.

Mutations in the NRF2-KEAP1 pathway is found to be related with therapeutic resistance and poor outcomes of non-small cell lung cancer (NSCLC). Here this group reports that cystine/glutamate antiporter system xc−, controlled by NRF2, can be non-invasively imaged by positron emission tomography thereby providing a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC.

Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.

In a previous clinical trial, the authors reported that SCFA-yielding biotherapy in adults with type 1 diabetes remodels the gut proteome and metabolome. Here, the show that colonization of the post-therapy microbiome into mice delayed diabetes and increased aryl-hydrocarbon receptor ligand and IgA production in the gut.

Schuermans et al. identify a causal relationship between the circulating proteins spondin-1 and atrial fibrillation and SPINT1 and coronary artery disease and show that adding proteomic data improves clinical risk factor-based cardiovascular risk prediction.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

The authors develop and validate mFISHseq, a spatially informed assay that tackles several unmet needs in breast cancer, including discordance in molecular subtyping and prognostic risk and identification of biomarkers predicting response to immunotherapies and antibody-drug conjugates.

Development of targeted MYC inhibitors for cancer therapy remains challenging. Here, the authors design an mRNA medicine which downregulates MYC gene transcription via epigenetic modification of MYC regulatory elements, showing significant antitumor activity in preclinical models of hepatocellular carcinoma.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Spatial gene expression provides insights into disease mechanisms. Here, authors benchmark eleven methods predicting spatial gene expression from histology images across five datasets and external validation, providing insights into clinical utility, challenges, and future directions.

Inflammatory monocytes are identified as important players in T cell restimulation in the tumour microenvironment.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

Mellman and colleagues present a multiomic single-cell analysis of the effects of combined anti-TIGIT and anti-PD-1 blockade on T cell populations trafficking from the draining lymph node to the blood and tumor.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.

Senescence can have beneficial and detrimental impact on cancer progression depending on the cellular context. Here the authors show that NRF2 regulates the senescence phenotype in malignant cells which consequently contribute to glioblastoma progression.

A lipid-nanoparticle-based formulation incorporating engineered lipids containing a blood–brain-barrier-crossing moiety effectively delivers mRNA to neurons and astrocytes following systemic administration in mice.

Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of hypertrophic cardiomyopathy. Here, the authors present an AAV9-based gene therapy system with an optimized expression cassette with minimal promoter and cis-regulatory elements that can ameliorate cardiac functions and prolong survival in a murine MYBPC3-deficient model.

Sawyers and colleagues describe an in vivo platform used to explore the dynamics and key factors of neuroendocrine lineage transformation. They find that Ascl1 depletion blocks plasticity and leads to cancer that is sensitive to castration.

Dysregulation of the TNF receptor signaling complex (TNF-RSC) promotes the onset of autoinflammatory conditions. Here the authors show that two adapter proteins, TANK and AZI2, mediate the recruitment of the kinase TBK1 to TNF-RSC to protect the mice from TNF-induced cell death and autoinflammation.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.

Here the authors present a large genetic study in East Asians that identifies 97 genetic regions linked to kidney function. These findings aim at better understanding chronic kidney disease in diverse populations.

Charles Serhan and colleagues report four new resolvins produced under inflammatory conditions that speed resolution of bacterial infection in mice.

A study of myeloid cells in gliomas, a type of brain tumour, used a factor-based computational framework to reveal four immunomodulatory gene-expression programs that are expressed across myeloid cell types, driven by microenvironmental cues and predictive of therapeutic response.

The mechanisms responsible for stimulating biogeochemical activity in the hyporheic corridor (HC) are poorly understood. Here, the authors find that previously unrecognized thermodynamic mechanisms regulated by groundwater-river water mixing may strongly influence HC biogeochemical and microbial dynamics.

In patients with drug-resistant tuberculosis who receive treatment with new and repurposed drugs, indicators of advanced disease and delayed conversion were associated with an increased risk of reversion. These factors may be targets for close monitoring.

Genome-wide association meta-analyses identify more than 350 loci associated with atrial fibrillation. A polygenic score derived from these results improves atrial fibrillation risk prediction compared to published clinical and polygenic scores.

Mutations in RAS oncogenes and related pathways are frequent in lung cancers. Here, the authors derive a RAS gene expression signature and a machine learning classifier to predict drug response and clinical outcomes in lung adenocarcinoma and other solid tumours, with improved performance over KRAS mutations alone.