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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.
Lou and colleagues describe the role of METTL16 in homologous recombination repair and demonstrate that PARP inhibition may be beneficial in the treatment of PDAC that is characterized by high METTL16.
Sengupta et al. show that the mesenchymal cell state in neuroblastoma is associated with heightened immunogenicity and anti-tumor immune responses compared with the adrenergic state, which is linked to sensitivity to immunotherapy in preclinical models.
Mu and colleagues describe a JAK–STAT signaling-dependent transition to a stem-like, multilineage state that is resistant to prostate cancer AR therapy and propose combinatorial targeting of JAK–STAT proteins to resensitize resistant tumors.
Aguirre-Ghiso and colleagues report that the pluripotency transcription factor ZFP281 promotes dormancy of early disseminated breast cancer cells in the lung by driving a mesenchymal-like gene expression program.
Shah and colleagues used machine learning to integrate features from computed tomography scan images, programmed death ligand-1 (PD-L1) immunohistochemistry and genomics into a multimodal predictor of response to anti-PD(L)1 in patients with NSCLC that outperformed single features such as tumor mutational burden.
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.
Langenau, Pinello and colleagues identify tumor-propagating stem cells in rhabdomyosarcoma that sustain tumorigenesis through integrated single-cell and functional characterization of patient-derived samples and preclinical models in vivo.
Yuan et al. demonstrate that cancer-associated fibroblasts in the pancreatic tumor microenvironment secrete nucleosides through autophagy in an NUFIP1-dependent manner, thereby inducing glucose consumption under glutamine-deprived conditions and promoting tumor growth.
Xi and colleagues show that BMP signaling has tumor-suppressive effects in ACVR1 wild-type diffuse intrinsic pontine glioma by modulating stemness via chromatin regulation of CXXC5, and demonstrate the therapeutic potential of this pathway using in vivo mouse models.
Neumüller and colleagues identify and characterize potent HER2 exon 20 insertion-selective inhibitors with efficacy, which preserve wild-type epidermal growth factor receptor signaling in preclinical models of non-small cell lung cancer in vivo.
Mabe et al. find that GD2 levels correlate with lineage plasticity in neuroblastoma and identify ST8SIA1 as the key enzyme in GD2 synthesis. EZH2 inhibition in mesenchymal neuroblastoma cells elevates ST8SIA1, synergizing with anti-GD2 antibodies.
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.
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.