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Batlle and colleagues report that after chemotherapy, Mex3a+ colorectal cancer cells represent drug-tolerant persister cells that lead to recurrence by downregulating the WNT–Lgr5+ stem cell program and adopting a transient regenerative state.
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.
Hata and colleagues identify lorlatinib analogs that overcome acquired therapy resistance to current ALK inhibitors and show their efficacy in preclinical models of non-small cell lung cancer bearing compound therapy-resistant ALK alterations.
Walle & Bajaj et al. assess the frequency of cytokine release syndrome upon COVID-19 vaccination in patients with cancer receiving immune-checkpoint inhibitors and find that while elevated cytokines levels are common, they do not manifest in detectable CRS.
Winter and colleagues demonstrate that metabolic adaptation to nutrient stress in the tumor microenvironment of pancreatic cancer leads to a dependency on IDH1, which is therapeutically actionable regardless of IDH1 mutation status.
Skokos and colleagues characterize human early-stage clear cell renal cell carcinoma with single-cell ATAC-seq and RNA-seq, identifying a spectrum of NFκB-promoted T cell dysfunction in the microenvironment and defining a pro-apoptotic signature.
Wood and colleagues report that the XPO1 inhibitor selinexor activates PI3Ky-dependent AKT signaling in AML via upregulation of P2RY2 and demonstrate a synergistic effect of combining selinexor with inhibition of prosurvival AKT signaling.
Raj and colleagues show that ERX-41 inhibits lipase-independent functions of LIPA and induces ER stress in different tumor types, providing a therapeutic strategy in PDX models of pancreas, ovarian and triple-negative breast cancer.
Fuchs and colleagues delineate a mechanism by which PARP11-mediated IFNAR1 loss sustains an immunosuppressive tumor microenvironment and show that PARP11 inactivation can enhance chimeric antigen receptor T efficacy in preclinical solid tumor models.
Wu et al. utilize multiparametric analysis of early-stage human NSCLC to characterize a population of Vδ1 T cells displaying a resident memory and effector memory phenotype, which were associated with ongoing remission.
Zhu and colleagues identify GREMLIN1 as an FGFR1 ligand that promotes plasticity and castration resistance in prostate cancer through regulation of MAPK signaling, and show that anti-GREMLIN1 antibody therapy synergizes with androgen deprivation.
Weaver and colleagues use breast cancer patient-derived organoids and mouse models to find an inhibitory role for the nuclear repressor NCOR2 in chemotherapy response and antitumor immunity, which can be targeted by blocking NCOR2–HDAC3 interaction.
Using genome-wide bisulfite sequencing of acute lymphoblastic leukemia subtypes, cell lines and healthy cells, Hetzel et. al. find that unlike most cancers, ALL has a highly methylated genome, which points to a distinct mode of epigenome regulation in this cancer type.
Armstrong and colleagues discover that combined targeting of IKAROS and MENIN is a therapeutic strategy for acute myeloid leukemia through disruption of essential leukemogenic transcriptional programs.
Li et al. demonstrate mitochondrial fission in macrophages as key for phagocytosis induced by therapeutic antibodies. They identify overexpression of GFPT2 as an inhibitor of the process and phase transition of the phagocytic machinery as its regulator.
Alborzinia et al. report that MYCN-amplified neuroblastoma undergoes ferroptosis in the absence of intracellular cysteine, suggesting a combination of cysteine depletion and concomitant GPX4 inactivation as a potential therapeutic approach.
Hongu et al. find that perivascular macrophages stimulate activation of the pro-metastatic vascular niche via tenascin C stimulation of TLR4 and show that combined TLR4 and VEGF inhibition prevents TNC-mediated metastatic vascular activity.
Danko and colleagues develop BayesPrism, a bulk RNA sequencing deconvolution tool to infer cell type composition and cell-specific expression levels across clinical cancer datasets.
Batlle and colleagues develop an organoid platform for functional antibody screening and identify a therapeutic bispecific antibody that binds EGFR and LGR5 and that shows efficacy across epithelial tumor patient-derived xenograft models in vivo.
Ji and colleagues demonstrate that metabolic reprogramming in SCLC underlies chemotherapy resistance, resulting in an actionable dependency on the mevalonate pathway in tumor cells, which can be targeted using statins to revert chemoresistance.