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  • CAR T cell therapies have made great strides in the clinic; however, multiple hurdles limit the efficacy of this approach for solid tumors. A new study has developed an optimized, dual-targeting CAR T cell that overcomes several of these challenges by enhancing T cell persistence and reducing therapy escape due to antigen loss.

    • Tiffany R. King-Peoples
    • Avery D. Posey Jr.
    News & Views
  • Pseudouridine is the most abundant RNA modification, but its biological role remains poorly understood. A study now finds dysregulated pseudouridine synthase PUS7 in glioblastoma and demonstrates that pharmacological inhibition of PUS7 leads to reduced tumorigenesis, which underpins the therapeutic potential of targeting epitranscriptomic regulators in cancer.

    • Virginia Morón-Calvente
    • Sandra Blanco
    News & Views
  • Combining radiation and immune checkpoint blockade is a promising treatment strategy, yet the mechanisms and optimal dosing strategies are not well known. A new study finds that a specific radiation dose can activate secretory club cells to promote the anti-tumor effects of radiotherapy combined with immunotherapy in NSCLC.

    • Ralph R. Weichselbaum
    • Sean P. Pitroda
    News & Views
  • Drug resistance may pre-exist or arise during therapy, but how precisely cancer treatment itself influences these processes is a major gap in the understanding of therapy resistance in cancer. A study of acute lymphocytic leukemia now provides direct evidence of thiopurine-induced mutations in the gene encoding the tumor suppressor p53 that result in multi-drug-resistant relapse.

    • Nikki A. Evensen
    • William L. Carroll
    News & Views
  • Immuno-oncology approaches have shown little efficacy against high-grade glioma, a devastating manifestation of brain cancer. A new study now finds a metabolic vulnerability in IDH1-mutant glioma that can be targeted to reprogram tumor-infiltrating macrophages and create a tumor microenvironment that is more responsive to immune-checkpoint therapy.

    • Marie Jo Halaby
    • Tracy L. McGaha
    News & Views
  • Institutional clinical data repositories provide a depth and consistency of data elements that is difficult to match even with data pooled from diverse sources. A study now demonstrates how real-world data and clinical encounters can be captured in an integrated ‘data story’ to enable continuous learning and hypothesis generation in oncology.

    • Joseph O. Deasy
    • Peter D. Stetson
    News & Views
  • Prostate cancer is largely unresponsive to immunotherapy. A new study finds elevated expression of the chemokine IL-8, or its mouse homolog Cxcl15, in prostate cancer after castration, which leads to the recruitment of immunosuppressive myeloid cells. Blocking tumor infiltration with these cells could improve the response to immune-checkpoint inhibition and androgen-deprivation therapy.

    • Ravi A. Madan
    • Claudia Palena
    News & Views
  • FTO, an m6A RNA demethylase, is known mainly as an oncoprotein in various cancer types. FTO is now shown to act as a cancer suppressor in a subset of epithelial tumors through an interplay between epithelial-to-mesenchymal transition and Wnt signaling.

    • Albertas Navickas
    • Hani Goodarzi
    News & Views
  • The DNA polymerase Polθ is synthetic lethal with homologous-recombination deficiency, but a lack of specific targeting compounds has limited its therapeutic potential. Two studies now describe first-in-class inhibitors of Polθ with in vivo efficacy and thus provide alternative therapeutic approaches to PARP inhibitors for cancers deficient in homologous recombination.

    • Thomas Helleday
    News & Views
  • Mutations in genes encoding epigenetic modifiers are frequent in acute myelogenous leukemia (AML) and have been proposed to cause AML via activation of oncogenes and repression of tumor suppressors. Two studies now identify unexpected oncogenic mechanisms and therapeutic vulnerabilities in AML arising from mutations in genes encoding the epigenetic regulators DNMT3A and ASXL1.

    • Koki Ueda
    • Ulrich Steidl
    News & Views
  • Two recent studies demonstrate how autophagy, in both tumor cells and host tissues, regulates anti-tumor T cell responses. These works add to accumulating evidence that inhibitors of autophagy could be used in combination with immunotherapy in certain cancer types.

    • Andrew Thorburn
    • Christina G. Towers
    News & Views
  • Cancer cells need to adapt their metabolic state to different microenvironments, particularly during metastatic spread, when they are exposed to the circulatory system as well as the distant organ. Two studies now show that upregulation of fatty acid synthesis is required for the formation of breast cancer metastasis in the lipid-poor environment of the brain.

    • Felix C. E. Vogel
    • Almut Schulze
    News & Views
  • Small-molecule kinase inhibitors have made major advances in cancer therapy, but their efficacy remains limited by intrinsic and acquired resistance. The expression and thermostability of the kinase CDK6 are now shown to mediate intrinsic resistance to CDK4/6 inhibitors and degraders across cancer types.

    • Signe Caksa
    • Andrew E. Aplin
    News & Views
  • Pharmacogenomic drug screening provides a promising platform for the discovery of anti-cancer drugs, in combination with biomarkers and mechanisms that confer therapeutic response. A study now pinpoints the mechanisms of sensitivity to dasatinib in T-ALL leukemia, identifying a T cell–differentiation switch that determines sensitivity to distinct drug modalities.

    • Anders Jacobsen Skanderup
    • Ramanuj DasGupta
    News & Views
  • Shedding light on the mechanisms that underlie a durable response to immunotherapy, a recent study evaluating long-term survivors of melanoma treated with immunotherapy finds that tumor-associated T cell clonotypes are sustained over years and persist as expanded, cytokine IFN-γ–expressing resident memory T cells in the skin, with effector memory counterparts in the blood.

    • Anusha-Preethi Ganesan
    • Christian H. H. Ottensmeier
    News & Views
  • The complexity of glioblastoma is becoming increasingly recognized. Three recent studies used single-cell approaches that integrate cellular states, transcriptional trajectories, and metabolic alterations to uncover multiple dimensions of cellular and molecular heterogeneity and provide a framework for additional functional investigation and therapeutic development.

    • Christopher G. Hubert
    • Justin D. Lathia
    News & Views
  • Metabolic reprogramming mediates resistance to therapy and rewires cancer-cell-signaling networks, paving the way to the discovery of enhanced treatment strategies through acquired vulnerabilities. A study now points to lipotoxicity dependent on Raf-1 kinase that occurs after activation of the liver receptor LXRα as a therapeutic intervention for the treatment of hepatocellular carcinoma.

    • Suchira Gallage
    • Jose Efren Barragan Avila
    • Mathias Heikenwalder
    News & Views
  • The diversity of tumor cell responses to cyclin-dependent kinase 4/6 (CDK4/6) inhibition in breast cancer is a question not yet fully addressed. A recent study defines the effects of CDK4/6 inhibition on chromatin organization and shows that remodeling of the cancer cell epigenome mediates some of the key biological effects of these targeted therapy agents.

    • Antoni Hurtado
    News & Views
  • Chronic pancreatitis is a risk factor for pancreatic cancer; however, the mechanisms underlying cellular susceptibility to oncogenic transformation are complex. A recent study reports a damage-associated progenitor cell state, controlled by the transcription factors KLF5 and members of the AP-1 family, that initiates tumorigenesis in mouse models of pancreatic cancer in which the proto-oncogene KRAS is altered.

    • Lindsay M. LaFave
    • Jason D. Buenrostro
    News & Views
  • Achieving depletion of regulatory T cells while sparing tumor-specific effector T cells has long remained an elusive goal of immunotherapy. A new study describing the development of an antibody to the cytokine receptor CD25 optimized to ensure depletion of regulatory T cells without blocking binding of the cytokine IL-2 will reinvigorate interest in this therapeutic avenue.

    • Gavin I. Ellis
    • James L. Riley
    News & Views