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Müller-Tidow and colleagues demonstrate that hotspot DNMT3A mutations found in clonal hematopoiesis and acute myeloid leukemia render cancer cells sensitive to the DNMT1 inhibitor azacitidine through focal DNA demethylation, viral mimicry and interferon activation.
Shilatifard and colleagues demonstrate gain-of-function mutations in ASXL1 that drive BAP1 stabilization and widespread epigenetic changes in myeloid neoplasms, and develop a chemical inhibitor with therapeutic potential for ASXL1-altered leukemia.
Platten and colleagues find that tryptophan metabolism by myeloid cells contributes to immunosuppressive microenvironment uniquely in IDH-mutant gliomas, which can be overcome by inhibiting this pathway in murine tumor models.
Amrolia and colleagues characterize the clonal origins of long-term persistent CAR T cells from the CARPALL trial using low-affinity CAR T cells mediating long-term anti-leukemic control in patients through TSCM-mediated responses.
Wong and colleagues show that LKB1-deficient lung tumors are sensitive to autophagy inhibition, which can restore impaired antigen presentation and antitumor immune responses, and propose dual targeting of ULK1 and PD-1 for these tumors.
Quail and colleagues demonstrate that neutrophil-derived ROS and extracellular traps (NETs) mediate breast cancer metastasis to the lungs by altering endothelial junctional adhesions, thus favoring vascular permeability and transendothelial migration of cancer cells.
Nik-Zainal and colleagues leverage CRISPR–Cas9 and whole-genome sequencing to examine mutational patterns following knockout of 42 human DNA repair genes. They further develop and validate a clinically relevant tool to detect mismatch repair-deficient tumors.
Song and colleagues report that in breast cancer, chemotherapy induces the IRENA lncRNA, which reprograms tumor suppressive macrophages to protumorigenic phenotypes and promotes chemoresistance.
Curtis and colleagues use multiplex spatial proteomics on longitudinal HER2-positive breast tumor biopsies through neoadjuvant therapy and develop a classifier that predicts pathological complete response, using on-treatment CD45 as a single biomarker.
Ferraro et al. report that fatty acid synthesis is needed for brain cancer metastasis and show that blocking this process by inhibiting fatty acid synthase reduces the metastatic growth of breast cancer cells in the brain.
Turk and colleagues analyze exceptional responders to checkpoint blockade for melanoma, and detect tissue-resident memory and effector memory T-cell clonotypes in skin and blood, respectively, up to 9 years after treatment.
Ellis and colleagues show that combination of EZH2 inhibition and anti-PD-1 can increase antitumor immune responses in typically ‘immune cold’ prostate cancer, by increasing EZH2-regulated dsRNA–STING–ISG response signaling.
Halmos, Goel and colleagues characterize the rates of SARS-CoV-2 seroconversion in patients with cancer and see higher IgG positivity associated with specific cancer types and therapy modalities.
Ishikawa and colleagues perform integrated genomic and drug-sensitivity screens with extensive PDX modeling and reveal combined XIAP and BCL2 inhibition as a vulnerability hub across AML genetic alterations.
Magrini et. al. study sarcoma development and antitumor immune response in complement-deficient murine hosts, demonstrating a role for the C3a–C3aR axis in promoting immunosuppressive macrophages.
Walsh and colleagues use prospective sequencing in a large cohort of pediatric patients with solid tumors to detect mutations in cancer predisposition genes and guide downstream clinical care.
Zender, Dauch and colleagues demonstrate that pharmacologically induced lipotoxicity by activating LXRα and Raf-1 inhibition provides a metabolic therapeutic strategy for hepatocellular carcinoma.
Eilers and colleagues report that Aurora-A suppresses transcription–replication conflicts in MYCN-driven neuroblastoma, a vulnerability that can be targeted with a combination of Aurora-A and ATR kinase inhibitors.