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PARP inhibitors, either alone or in combination with bevacizumab, have regulatory approval as maintenance therapy following response to first-line platinum-based chemotherapy. Here this group reports SOLACE2 trial investigating whether combining olaparib with low dose cyclophosphamide treatment improves progression-free survival, comparing to olaparib monotherapy alone, in platinum-sensitive recurrent ovarian cancer.

Plasma p-tau217 tests used to develop clocks that predict when cognitively unimpaired individuals would develop symptoms of Alzheimerʼs disease.

Here the authors show that persistent antigen stimulation drives the generation of CD8⁺ tissue-resident exhausted T cells with distinct developmental origins, function and therapeutic responsiveness when compared to CD8⁺ tissue-resident memory T cells.

The study shows that vaccination with two doses of recombinant zoster vaccine is associated with a 51% reduction in the risk of dementia in adults aged ≥65 years. Reduction in risk is comparable across subgroups and remains statistically significant after accounting for healthy vaccinee bias.

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.

Conventional type 1 dendritic cells (cDC1) can boost the precursor exhausted T cell population thought to be essential for efficacy of immune checkpoint therapy. Here the authors enhance this cellular network using Flt3L to expand cDC1s and then map the movement of T cells and DCs between tumors and lymph nodes.

KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.

A combination of mouse model data and data from a randomized phase 2 trial in patients with breast cancer in remission demonstrates feasibility, safety and a reduction in residual tumor cells following treatment with hydroxychloroquine and/or everolimus.

Roland et al. report the results of a randomized, non-comparative phase 2 trial of neoadjuvant nivolumab or a combination of nivolumab and ipilimumab in patients with resectable retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

There is increasing evidence of a functional interaction between acute myeloid leukemia (AML) and immune cells, influencing disease outcome. Here the authors study how distinct oncogenes differentially affect the host immune response to leukemic cells in preclinical models of AML.

The extent to which COVID-19 vaccination protects against long COVID is not well understood. Here, the authors use electronic health record data from the United States and find that, for people who received their vaccination prior to infection, vaccination was associated with lower incidence of long COVID.

Inactivating PPP2R1A mutations correlate with better survival after immune checkpoint blockade in patients with ovarian clear cell carcinoma, suggesting that targeting the phosphatase 2A (PP2A) pathway may represent an effective startegy for improving responses to immunotherapy.

A modular anti-albumin nanobody conjugated to a STING agonist enhances antitumour immunity by improving pharmacokinetics, tumour accumulation and immune responses, inhibiting murine tumour growth and enhancing cancer immunotherapies.

The role of rare pathogenic/likely pathogenic (P/LP) germline variants in pediatric central nervous system (CNS) tumour development remains poorly understood. Here, the authors investigate the prevalence and clinical significance of germline P/LP variants in cancer predisposition genes across 830 CNS tumour patients.

Serine metabolism is essential for leukemogenesis and stemness in acute myeloid leukemia (AML). Here the authors show that targeting IGF2BP3 disrupts the serine synthesis pathway in AML cells in an RNA N⁶-Methyladenosine modification dependent manner, sensitizing AML cells to serine and glycine deprivation.

Solid tumors often resist immunotherapy due to an immunosuppressive tumor microenvironment. Here, the authors develop CancerPAM, a multiomics CRISPR pipeline that enables tumor-specific cytokine expression to boost immune infiltration and CAR T cell efficacy in neuroblastoma.

Epiphytic plants are a highly biodiverse group of tropical species at high risk of extinction from climate change. In this study, a multi-year transplant experiment, paired with distributional surveys in Central America, shows that many of these species may not survive projected changes in climate, providing empirical evidence for hypotheses raised by previous studies.

A recombinant antivenom composed of eight nanobodies provides broad protection against venom-induced lethality and dermonecrosis in mice challenged with venoms from cobras, mambas and rinkhals snakes.

Pancreatic cancer progression is driven by a switch from HNF4G-driven transcriptional activity in primary disease to FOXA1-mediated transcription in the metastatic setting.

Disrupting the normal maturation of the infant gut microbiota induced late-onset sepsis in mice, which could be prevented by administering specific bacteria.

Shah and colleagues develop a multimodal data integration framework that interprets genomic, digital histopathology, radiomics and clinical data using machine learning to improve diagnosis of patients with high-grade ovarian serous carcinoma.

Natural killer (NK) cells are critical innate immune effector cells but during chronic inflammatory contexts their function and fitness may become impaired. Here the authors implicate the cytokine IL-35 in the conversion of NK cells towards ILC1-like cells with features of tissue residency and impaired functionality.

Panzeri et al. use a Trim28^+/D9 mouse model with intrinsic developmental heterogeneity to show that ‘heavy’ and ‘light’ developmental morphs exhibit different timing, type and severity of cancer, linked to a relevant DNA hypomethylation signature.

In an analysis of adult patients with hematologic malignancies who received anti-CD19 chimeric antigen receptor T cell therapy, baseline gut microbiome composition was correlated with clinical response and treatment with broad-spectrum antibiotics in the four weeks prior to infusion was associated with worse survival and increased neurotoxicity.

Fecci and colleagues show that tumor cells having lost MHC-I, a major mechanism of immune escape, are amenable to killing by CD8⁺ T cells through an MHC-I-independent, alternative pathway via NKG2D and NKG2DL interaction and granzyme.

Genome-wide association studies (GWAS) of deep learning-derived measurements of aortic valve function, along with multitrait analyses incorporating disease-based GWAS, identify 166 genetic loci associated with aortic valve function or aortic stenosis.

Using whole-genome and single-cell RNA sequencing data of patients with multiple myeloma treated with carfilzomib, lenalidomide, dexamethasone and daratumumab, Maura et al. identify distinct genomic drivers and microenvironment changes affecting outcome.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

A highly potent and selective small-molecule catalytic inhibitor of the protein lysine methyltransferase NSD2 shows therapeutic efficacy in preclinical models of KRAS-driven pancreatic cancer and lung cancer.

Glioblastoma stem cells co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on glioblastoma stem cell maintenance and extrinsic effects on immune response.

Genome-wide CRISPRi screens for modulators of androgen receptor (AR) protein levels using live-cell quantitative endogenous AR fluorescence reporters identify PTGES3 as a new regulator of AR stability and function in prostate cancer.

Glucocorticoids, such as dexamethasone, are used as anti-inflammatory and immunosuppressive drugs, however patients may exhibit resistance or side effects. Here the authors propose that a dexamethasone related neutrophil-specific DNA methylation index can be used as a marker of glucocorticoid exposure and response and as a prognostic factor in brain tumor survival.

The role of the tumour microenvironment in the response to immune checkpoint inhibitors in metastatic melanoma remains poorly understood. Here, single cell profiling of metastatic melanoma samples identifies associations of the mature dendritic enriched in immunoregulatory molecules subtype with immunotherapy response.

Using viral barcode tracing to detect interactions between glioblastoma cells and non-malignant astrocytes in patient samples, investigators discovered a pathway that reduces tumour-specific immunity and identified potential therapeutic targets.

Phenotype switching is a form of plasticity that allows melanoma cancer cells that leave the primary tumour to invade secondary sites, to switch from an invasive to a proliferative state. Here the authors identify EDN3, and its synthetic enzyme ECE2, as a regulator of melanoma plasticity in the microenvironment.

Peptide-based cancer vaccines require epitopes for both CD8+ and CD4+ T cells. Here the authors report the long-term outcomes of a randomized phase II trial (NCT00118274) in patients with melanoma designed to evaluate a class I MHC-restricted peptide vaccine plus one of two “helper” peptide preparations to stimulate CD4+ T cells, either non-specific help or melanoma-specific help.

Identifying genes involved in MYC-driven lymphoma reveals therapeutic vulnerabilities. Here, the authors show by using CRISPR knockout screens in primary cells in vivo that the GATOR1 complex suppresses MYC-driven lymphomagenesis, and that GATOR1-deficient lymphomas are sensitive to mTOR inhibitors.

A substudy of the CodeBreaK 101 trial, this phase 1b trial testing the KRAS-G12C inhibitor sotorasib with an anti-EGFR antibody shows an acceptable safety profile of this combination and encouraging preliminary clinical efficacy in patients with chemotherapy-refractory colorectal cancer.

AnnexinV has been shown to bind phosphatidylserine expressed by chemotherapy-induced apoptotic cells increasing their immunogeneicity. Here, the authors demonstrate in a preclinical tumor model that fusing tumor-antigen peptide to Annexin V enhances its efficacy when administered after chemotherapy and with other immune checkpoint inhibitors.

A subset of pediatric gliomas harbour alterations in fibroblast growth factor receptor (FGFR)-family proteins. Here, the authors characterise the genomic landscape of 11,635 gliomas across ages and use isogenic model systems to explore the underlying biology of FGFR1-altered gliomas and potential therapeutic vulnerabilities.

Using pancreatic organoids and genetic mouse models, Antonucci et al. show that cellular stress activates an NRF2–EZH2 epigenetic axis leading to metabolic reprogramming and subsequent malignant transformation of KRAS-mutant benign lesions.