Cancer research

Fendt and colleagues find that pre-metastatic niche formation and a high-fat diet increase palmitate availability in future organs of metastases and show that breast cancer cells use palmitate to generate acetyl-CoA, acetylate the NF-κB subunit p65 and induce pro-metastatic signaling.

Zou et al. show that SMARCD3 regulates DAB1 activity and Reelin signalling in the developing cerebellum, which can be hijacked to promote medulloblastoma cell migration and metastatic dissemination.

Achreja et al. develop a framework to identify collateral lethalities in cancer, uncovering MTHFD2 as a collateral lethal gene in UQCR11-deficient ovarian tumours.

A study of patients with breast cancer and mouse models demonstrates that most circulating tumour cells are generated during the rest phase of the circadian rhythm, and that these cells are highly prone to metastasize.

Acetyl coenzyme A (acetyl-CoA) is a key metabolite in carbohydrate and lipid metabolism and plays a role in signalling through protein acetylation, and the dysregulation of these pathways is a hallmark of various cancers. In this Review, Guertin and Wellen give an overview of acetyl-CoA metabolism in health and in cancer and discuss emerging therapeutic strategies for targeting metabolic pathways involving acetyl-CoA.

Naked mole rats are found to be resistant to cancer development through dampened inflammatory response due to genetically determined impaired necroptosis, with essential necroptosis genes RIPK3 and MLKL containing mutations causing premature stop codons.

γδ T cells contribute to the response to immune checkpoint blockade treatment in patients with HLA-class-I-negative DNA mismatch repair-deficient colon cancers. .

In preclinical studies, Hutt, Loi and colleagues find that mice treated with checkpoint blockade have impaired ovarian function and reserve, associated with increased immune infiltrate, raising considerations about fertility implications for female patients.

Cancer immunotherapies can be limited by terminally dysfunctional T cells in the tumor microenvironment. Here the authors present a model of stable human T cell dysfunction to show that TGFβ contributes to this terminal dysfunction which can be therapeutically inhibited by simultaneously blocking TGFβ1 and boosting bone morphogenetic protein (BMP) signaling.

Bae et al. engineer mesenchymal stem cells to express and deliver IL-2 to tumour-infiltrating lymphocytes, leading to activation and expansion of CD8⁺ T cells and improved tumour control, overcoming adaptive resistance to immune checkpoint blockade.

This Review explains how natural killer (NK) cells promote immunity to tumours. The authors cover the therapeutic approaches that are being developed to mobilize NK cells in patients with cancer, including NK cell activators, checkpoint blockade, cellular therapies, and bispecific and trispecific NK cell activating antibodies.

Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.

A molecular taxonomy for prostate cancer reveals a subtype associated with copy-number loss found in African and European populations that predicts poor outcomes and two subtypes—one associated with high mutational noise and one with copy-number gain—specific to African populations.

A combined modelling and tumour analysis approach is used to study the temporal and spatial patterns of subclone evolution in the TRACERx renal study. Studying the tumour shape and spatial features of clonal diversity in early-stage tumours may allow the prediction of tumour progression and patterns of subclone diversification over time.

In a phase 2 trial, monitoring tumor resistance mutations in blood using liquid biopsies allowed rationally guided subsequent therapy with anti-EGFR antibodies in patients with colorectal cancer.

In this Review, the authors discuss our latest understanding of extrachromosomal DNA (ecDNA), a type of circular DNA element commonly found in cancers. They discuss ecDNA properties, including oncogene amplifications and transcriptional hub formation, as well as opportunities for therapeutic interventions.

A phase I dose-escalation trial of GD2-CAR T cells in children and young adults with diffuse midline gliomas to assess the feasibility of manufacturing, safety and tolerability, and to preliminarily assess efficacy.

Tomlins et al. develop an Immunotherapy Response Score (IRS) to predict clinical benefit from checkpoint inhibition across solid tumors. IRS integrates TMB and gene expression, is evaluable from FFPE material, and is predictive for real-world progression-free survival and overall survival in patients receiving PD-1/PD-L1 blockade therapy.

Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC.

Telli and colleagues present a phase II clinical trial of the PARP inhibitor talazoparib in patients with solid tumors and show that the drug has activity in patients with breast cancer with mutations in other homologous recombination pathway genes beyond BRCA1 and BRCA2.

Intratumoral injection of the oncolytic virus talimogene laherparepvec (T-VEC) during weekly paclitaxel before neoadjuvant doxorubicin and cyclophosphamide led to clinical benefit and was well tolerated in patients with stage 2–3 triple-negative breast cancer.

Through a community-driven competition, the PANDA challenge provides a curated diverse dataset and a catalog of models for prostate cancer pathology, and represents a blueprint for evaluating AI algorithms in digital pathology.

Either alone or in combination, chemotherapy remains the mainstay treatment for most human malignancies. This treatment modality is associated with a high burden of chemotherapy-associated adverse events (CAAEs) that greatly affect patients because of their considerable morbidity, mortality and costs. Kuderer et al. discuss the pathophysiology, management and risk factors of the most common acute CAAEs with a major effect on survival, quality of life, function and/or continuation of optimal therapy.