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RNA-based viruses can be engineered to express artificial microRNAs (amiRNAs). Here, the authors identify a candidate amiRNA that confers a replicative advantage to oncolytic viruses, enhancing their anticancer potency, and show that intercellular transfer of extracellular vesicles carrying the amiRNA promotes bystander killing of uninfected cancer cells.

Ataxia telangiectasia and Rad3-related kinase (ATR) is a rational radiosensitization target. This trial evaluates the combination of the ATR inhibitor, ceralasertib, with palliative radiotherapy in 27 patients with advanced solid tumors.

Oncolytic virus holds potential as a cancer therapy, but further optimization is desirable. Here the authors screen existing drug to find talazoparib, a PARP inhibitor, synergizing with reovirus type 3 Dearing (RT3D) to induce cancer cell apoptosis, anti-tumor immunity, as well as control of primary and rechallenge tumor in mouse models.

Pattern recognition receptors (PRR) critically modulate innate immunity. Here the authors show in cancer cells that interferon responses and anti-tumor immunity activated by dsRNA-induced PRR signaling is enhanced by palbociclib-induced ER stress, with epigenetic changes and altered antigen presentation potentially contributing to this effect.

Centromere fragility can drive tumourigenesis, so protective mechanisms are important. Here, the authors suggest that the PBAF chromatin remodelling complex, which is frequently misregulated in cancer, helps to maintain the integrity of centromeres.

Cancer vaccines are frequently designed to increase the immune response toward one or more of the few known tumor-associated antigens (TAAs). Kottke et al. describe an alternate approach to enhancing anti-tumor immune responses without the need for identification of specific TAAs. They show that systemic delivery of a vesicular stomatis virus–based cDNA library derived from normal tissue induces immune responses that impede growth of tumors of the same tissue type in mice.

Immune checkpoint blockade can result in good outcomes in patients with metastatic head and neck squamous cell carcinoma (HNSCC), but not those with locally advanced disease. Here, the authors demonstrate that the addition of anti-NKG2A and anti-PD-L1 blockade to ATR inhibition and radiotherapy in the adjuvant setting can induce a robust antitumour immune response in mice.

Oncolytic viruses create an inflamed tumour microenvironment allowing T cells to respond to immune checkpoint blockade therapy more efficiently. Authors here show that in a hepatocellular carcinoma model, a dominant anti-viral rather than anti-tumour T cell response is elicited by an oncolytic vesicular stomatitis virus, unless the virus is designed to express tumour antigens, which restores therapeutic benefit.

Oncolytic viruses, such as vesicular stomatitis virus (VSV), are a promising class of cancer therapeutics. Here the authors report that a mutation in the CSDE1 gene renders cancer cells resistant to VSV replication and oncolysis, but a mutation-derived escape-associated neoantigen could be exploited for immunotherapy against treatment-resistant tumors.

DNA mutations induced by dysregulated APOBEC3 expression are associated with tumour-progression and therapeutic resistance, but also with the generation of neoepitopes. Here, the authors show that APOBEC3 function can be exploited in a vaccine setting to generate heteroclitic neoepitopes, enhancing sensitivity to immunotherapy.

Vaccination with a virus-expressed cDNA library derived from normal prostate cells can cure established prostate cancer in mouse models. Pulido et al. extend this approach and identify specific tumor-associated antigens from tumor-derived virus-expressed cDNA libraries that can be used in combination to cure established melanoma in mice.

Detecting tumor recurrences early and developing therapies capable of targeting recurrences that resist frontline therapy could be of enormous benefit to patients with cancer. Using mouse tumor models, Richard Vile and colleagues find a cytokine signature associated with very early stage recurrences, as well as evidence that the recurrent tumors are resistant to innate immune responses. By targeting the altered phenotype of the recurrent tumors, the researchers cured the mice of cancer, suggesting new avenues for research into human cancer recurrence.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

In a GWAS study of 32,438 adults, the authors discovered five novel loci for intracranial volume and confirmed two known signals. Variants for intracranial volume were also related to childhood and adult cognitive function and to Parkinson's disease, and enriched near genes involved in growth pathways, including PI3K-AKT signaling.

Tumour fibroblasts influence oncolytic viral therapy. Arwert et al. show that transcytosis of cancer cells into fibroblasts activates STING and IRF3 to upregulate interferon-β1, eliciting a transcriptional program to reduce the effectiveness of oncolytic viral therapy.

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.

This Review focuses on the role of tumour cell-autonomous signalling after radiotherapy. It describes how radiotherapy, through its immunomodulating effects, might be combined with immune checkpoint inhibitors and other immunotherapies and how DNA damage response inhibitors in combination with radiotherapy may be used to further augment this approach.