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Yarchoan and colleagues present a single-arm phase 1 clinical trial of cabozantinib with immune checkpoint inhibition for patients with hepatocellular carcinoma. Using high-dimensional spatial analysis, they identify immune features enriched in responders.
Zhou and colleagues demonstrate that thiopurine chemotherapy in mismatch repair-deficient ALL cells leads to R248Q TP53 mutations and clonal selection that favors on-treatment ALL relapse and chemoresistance.
Morin and colleagues develop a data-integration framework capable of performing continuous learning from electronic health records on clinical, social and demographic data collected over a decade to estimate pan-cancer survival prognosis.
Drake and colleagues demonstrate that castration in prostate cancer models promotes IL-8 secretion and immunosuppressive myeloid-derived suppressor cell migration, and that inhibiting this axis in combination with checkpoint blockade can mitigate tumor progression.
Obenauf and colleagues report that acquired resistance to BRAF and MEK inhibitors in melanoma confers cross-resistance to immune checkpoint blockade by fostering a cancer cell–instructed, immune-evasive tumor microenvironment.
Manczinger and colleagues define ‘promiscuity’ as a feature of HLA-I alleles representing peptide repertoire breadth; promiscuous alleles may promote a more tolerant tumor microenvironment and negatively impact tumor immune surveillance.
Kharas and colleagues identify the RNA-binding proteins RBMX and RBMXL1 as AML tumor promoters that alter chromatin compaction and hence cell survival via transcriptional regulation of the heterochromatin protein encoded by CBX5.
Enver and colleagues report that epigenetic cell state, rather than genetic diversity, drives bottleneck selection of subclonal genotypes during induction chemotherapy in childhood B-cell precursor acute lymphoblastic leukemia.
Huber and colleagues utilize a multi-omic analytical pipeline to define an axis of proliferative drive involving mTOR, MYC and OXPHOS metabolic activity that is associated with disease heterogeneity and outcome in clinical cohorts of CLL.
Fuks and colleagues report that downregulation of the FTO m6A RNA demethylase activates the Wnt pathway, promoting EMT-mediated progression of epithelial tumors and conferring sensitivity to Wnt inhibitors.
D’Andrea and colleagues identify the antibiotic novobiocin as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors in vivo, including these with acquired PARP inhibitor resistance.
Bild and colleagues identify convergent clonal evolution mechanisms through single-cell genomic analyses, explaining therapy resistance in patients with early-stage breast cancer treated with endocrine and CDK4/6 therapy in the FELINE trial.
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.