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In a phase 1 trial testing healthy donor fecal microbial transplantation with immune checkpoint blockade in patients with previously untreated renal cell carcinoma, treatment was safe with an encouraging response signal and microbiome analyses, suggesting specific donor taxa associations with toxicity.

Rathmell and colleagues show that metabolic reprograming of regulatory T cells is associated with severity of critical illness in patients with and without sepsis.

Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

Myelin damage in multiple sclerosis can be detected up to 7 years before symptoms, with early immune pathway activation and a 21-protein panel showing promise for presymptomatic diagnosis.

The cryo-EM structure of the herpes simplex virus helicase–primase (HP) complex informs about the mechanism of action of HP inhibitors pritelivir and amenamevir, which are drugs of clinical relevance.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

SpaceX’s Inspiration4 mission sent an all-civilian crew into orbit to study physiological, neurovestibular and neurocognitive changes in the astronauts and found that short-duration civilian space missions do not pose a major health risk.

The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes.

The extent of antibody protection against SARS-CoV-2 remains unclear. Here, using a cohort of 120 seroconverted individuals, the authors longitudinally characterize neutralization, Fc-function, and SARS-CoV-2 specific T cell responses, which they show to be prominent only in those subjects that elicited receptor-binding domain (RBD)-specific antibody titers above a certain threshold, suggesting that development of T cell responses to be related to anti-RBD Ab production.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

Wang et al. present T cell receptor sequencing of serial tumor and blood samples from TIL-treated patients with non-small cell lung cancer, identifying tumor-reactive clonotypes expressing dysfunctional programs in patients lacking clinical benefit.

Integrating gene expression across tissues is crucial for understanding coordinated biological mechanisms. Viñas et al. present a neural network for multi-tissue imputation of gene expression, exploiting the shared regulatory architecture of tissues.

The impact of tumor intrinsic and immune alterations on disease progression in patients with Waldenstrom’s Macroglobulinemia (WM) remains to be characterized. Here, the authors perform single-cell RNA-sequencing and identify distinct tumor subtypes, tumour microenvironment features and potential therapeutic vulnerabilities in patients with WM.

The genetic basis of gastric cancer, the fourth most common cancer worldwide, remains poorly understood. Here, the authors sequence and analyse the exomes and transcriptomes of primary gastric tumours and cell lines, and identify a ZAK kinase isoform that may have an oncogenic role in gastric cancer.

Rhine et al. find that neuronal aging leads to widespread dysregulation of RNA biology, including mislocalization of splicing proteins like TDP-43, chronic cellular stress and reduced resiliency.

Patients with partial recombination-activating gene (RAG) deficiency (pRD) present variable late-onset autoimmune clinical phenotypes. Walter and colleagues identified a restricted primary B cell antigen receptor repertoire enriched for autoreactivity and clonal persistence in pRD. They described dysregulated B cell maturation with expansion of T-bet⁺ B cells revealing how RAG impacts stringency of tolerance and B cell fate in the periphery.

Maatz, Lindberg et al. identify molecular alterations and immune response changes in endomyocardial biopsies from patients with myocarditis after COVID-19 infection, after anti-COVID-19 vaccination or from non-COVID-related causes.

Mansoor Sheik-Bahae, an exceptionally inventive scientist who made important contributions to nonlinear optics, optical refrigeration and laser science, passed away in July 2023, aged 67. He will be cherished for his sharp intellect, good humour, warm heart and the scientific legacy he leaves.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

Here, Fry and colleagues examine the impact of antigen experience on subsequent CD8⁺ CAR T cell activity during the antileukemia response and show that RUNX2 overexpression enhances antitumor activity of these cells.

IL-27 promotes tumour control by preventing dysfunction and enhancing cytotoxicity of tumour-specific CD8⁺ T cells.

Individuals with long COVID show marked biological changes in cortisol and immune factors relative to convalescent populations.

Mast cells are tissue-resident immune cells important for clearance of parasitic worms but also mediating allergic reactions. Here Joulia et al. show that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens to increase efficiency and minimize off-target effects.

The Cancer Genome Atlas Research Network report integrated genomic and molecular analyses of 164 squamous cell carcinomas and adenocarcinomas of the oesophagus; they find genomic and molecular features that differentiate squamous and adenocarcinomas of the oesophagus, and strong similarities between oesophageal adenocarcinomas and the chromosomally unstable variant of gastric adenocarcinoma, suggesting that gastroesophageal adenocarcinoma is a single disease entity.

In the dose-escalation part of the ongoing phase 1/2 LIBRA4 trial, patients with relapsed/refractory peripheral T cell lymphoma received T cell antigen receptor beta-chain constant domain 1 (TRBC1)-targeted chimeric antigen receptor T cell therapy, showing limited toxicity and encouraging preliminary clinical responses.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Combining analysis of host proteome and transcriptome perturbations induced by tumour virus proteins with ongoing genome-wide studies of cancer facilitates the prioritization of cancer genes.

The detection of hypocretin-specific autoreactive CD4⁺ and CD8⁺ T cells in patients with narcolepsy reveals the autoimmune aetiology of this disorder.

Adoptive cell therapy with tumor-infiltrating lymphocytes in metastatic lung cancer patients is safe and elicits antitumor activity, including ongoing complete responses, in association with polyclonal T cell responses against tumor antigens.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.