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The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

The IRE1α-XBP1s pathway has been implicated in the regulation of anti-tumor immunity. Here the authors show that IRE1α is increased in prostate cancer (PCa) and that its inhibition reprograms the tumor microenvironment, promoting anti-tumor immune responses in PCa preclinical models.

Xuling Chang et al. study whether low frequency variants are associated with leukocyte telomere length and whether these variants predispose to incident cancers and mortalities among East Asians. They find that three East Asian specific variants at POT1, TERF1 and STN1 loci are associated with leukocyte telomere length and report a mechanistic pathway linking TERF1, leukocyte telomere length and incident colon cancer.

The behavior of exosomes in vivo is not completely elucidated. Here the authors develop a genetically engineered mouse model (ExoBow) to trace the distribution of exosomes, showing local and inter-organ communication networks, either specific or shared between healthy pancreas and pancreatic ductal adenocarcinoma.

It has been suggested that targeting the PD-1/PD-L1 axis can increase the anti-tumor properties of chimeric antigen receptor (CAR)-T cells. Here the authors report that CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.

A substudy nested within a double-blind cluster-randomized controlled trial in Bangladesh shows that drinking chlorinated water had relatively minor impacts on children’s gut microbiome development in this setting.

SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57^Kip2.

A role for the serpin maspin has been described in both development and cancer. In this study, the authors demonstrate that maspin knockout mice develop normally and that maspin does not function as a tumour suppressor, suggesting that another gene at the maspin locus may be responsible for this activity.

An individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA-based neoantigen vaccine is safe and well tolerated in patients, warranting further studies to test its potential to rescue response to checkpoint blockade in tumors of low immune reactivity.

3’ untranslated regions (3’UTRs) play a crucial role in regulating gene expression, but our 3’UTR catalogue is incomplete. Here, the authors develop a machine learning-based framework to predict previously unannotated 3’UTRs in 39 human tissues.

Franzoso and colleagues show that NF-κB protects cells from nutrient-starvation-induced necrosis by upregulating mitochondrial respiration through increased p53-dependent expression of the SCO2 enzyme. Conversely, inhibition of NF-κB results in increased aerobic glycolysis, known as the Warburg effect, thus promoting oncogenic transformation, and affects metabolic adaptation during tumorigenesis in vivo.

HACE1 is an E3 ligase that promotes degradation of the GTPase Rac1. Here Daugaard et al. show that HACE1 inhibits the activity of Rac1-dependent NADPH oxidase complexes, which reduces the production of cellular reactive oxygen species and cell cycle progression.

With aging, the immune system undergoes severe changes that impact health in numerous ways. For a comprehensive, translational analysis of these alterations, Krishnarajah et al. here provide profiling of immune cell populations across 12 tissues from young and old mice.

Chafino et al. investigate plasma biomarkers to identify metabolic dysfunction-associated steatotic liver disease (MASLD) in youth with vertically acquired HIV. Plasma metabolomics and gut microbiome analyses reveal ursodeoxycholic acid and specific triglycerides as key molecules in a predictive model for MASLD.

A deep learning model detects low frequency mosaic variants with improved accuracy.

Exosomes improve the delivery of siRNA to mutant KRAS in the pancreatic tumours and bypass immune clearance better than artificial liposomes, probably owing to enhanced macropinocytocis and presence of CD47 on exosomes, respectively.

Deletion of BECLIN1 in mice leads to fatal intestinal disruption and compromised gut barrier integrity. This study establishes that BECLIN1 is essential for intestinal homeostasis and uncovers its role in endocytic trafficking in this process.

Two spider toxins are shown to target the Na_v1.1 subtype of sodium channel specifically, shedding light on the role of these channels in mechanical pain signalling.

How γδ T cells 'see' antigen is poorly defined. Déchanet-Merville and colleagues demonstrate that a subset of γδ T cells functionally recognize the stress-associated self molecule EPCR on both virus-infected and transformed cells.

Insights into the effects of targeted therapies, conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical responses in patients.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.

In this Perspective, Holder et al. discuss the limitations of current predictive biomarkers of response to immune checkpoint inhibitors and the need to further explore static, dynamic and patient-specific biomarkers using novel tools, such as machine learning and consortia-level initiatives.

The p53 pathway is deregulated in almost all tumours making it a prime target for new cancer drug development. This Review discusses the new approaches to drug discovery that are currently being used to target the p53 pathway and the progress made with the drugs that have been developed so far.

Adam Shlien, Peter Campbell, Uri Tabori and colleagues report genome and exome sequencing of biallelic mismatch repair deficiency cancer samples from 12 children, including 10 high-grade gliomas. The hypermutational signature of the malignant glioma samples was consistent with a driver role for observed mutations in DNA polymerases ɛ or δ.