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  • Acute myeloid leukemia (AML) is an aggressive hematological cancer with limited treatment options. A study now provides compelling data and develops a therapeutic approach of targeting AML with a prolyl hydroxylase inhibitor, a strategy based on the sensitivity of myeloid cells to modulation of the transcription factor HIF.

    • Darragh Flood
    • Cormac T. Taylor
    News & Views
  • At present, six CAR-T therapies are FDA approved to treat hematological cancers, but not all patients respond. A new study has developed a multidimensional functional profiling method to screen CAR-T cells from patients with large B cell lymphomas in clinical trials and identified a T cell subset associated with successful clinical response.

    • Kevin P. Letscher
    • Sai T. Reddy
    News & Views
  • Tumor fibrosis is known to suppress anti-tumor immunity. A new study now highlights the role of tumor-associated macrophages in coordinating fibrosis-mediated metabolic changes in tumors, restricting cytotoxic T cell responses and contributing to tumor growth.

    • Matthew D. Perricone
    • Costas A. Lyssiotis
    News & Views
  • T cell receptor (TCR)-engineered T cells offer great promise for targeting tumor antigens in cancer therapy. A synthetic fusion protein termed 80BB, which can simultaneously activate the CD28 and 4-1BB co-stimulatory pathways, is now shown to enhance overall functionality of therapeutic TCR/CD3-dependent T cells in an antigen-agnostic manner.

    • Julia Höbart
    • Jürgen Ruland
    News & Views
  • Targeted therapies that use small-molecule inhibitors for the treatment of T cell blood cancer exist only for certain subtypes, and the development of immunologically based CAR T cell therapies has been challenging. A study now exploits the fact that malignant T cells express one of two T cell receptor-β variants and investigates strategies for targeting these malignant cells while sparing half of the non-malignant T cells.

    • Charles E. de Bock
    • Jan Cools
    News & Views
  • Gemcitabine is a widely used chemotherapy drug that acts by targeting DNA replication. Understanding why many tumors are unresponsive to gemcitabine is a clinical challenge. A new study in Nature Cancer reports that upregulation of the cytidine deaminases APOBEC3C and APOBEC3D facilitates resistance to gemcitabine by protecting cells against DNA replication stress.

    • John Maciejowski
    • Taha Mohamed
    News & Views
  • Sarcomas are heterogeneous connective tissue tumors that occur at various anatomic sites and are generally difficult to treat. Cell states in sarcoma ecosystems are now shown to be conserved across multiple subtypes and associated with response to immunotherapy and patient outcome.

    • Johanna Wagner
    • Stefan Fröhling
    News & Views
  • Arginine methylation is crucial for tumor maintenance. PRMT9 levels are elevated in acute myeloid leukemia, and its inhibition eradicates leukemia by diminishing arginine methylation of proteins involved in DNA damage response and RNA translation. This activates the cGAS–STING pathway, which triggers immune responses directed against leukemia. Epigenetic targeting of DNA-damage-response mechanisms may bolster anti-tumor immunity.

    • Antonella Santoro
    • Raffaella Di Micco
    News & Views
  • A study reports that survivors of childhood cancer age faster than healthy controls and have increased risk of frailty and death; however, heterogeneity in outcomes was present, indicating inequities in risk. Knowledge about aging in high-risk groups holds the potential to identify interventions to improve survivorship outcomes.

    • Judith E. Carroll
    • Jeanne S. Mandelblatt
    News & Views
  • Effectively targeting deregulated KRAS signaling remains an unmet clinical need, as current approaches commonly lead to the development of chemoresistance in clinical settings. ADAM9-mediated lysosomal KRAS degradation is now shown to counteract PDAC chemoresistance independently of mutational status.

    • Laura Leonhardt
    • Matthias Hebrok
    News & Views
  • Identifying which patients will benefit most from immune checkpoint blockade (ICB) is an important clinical challenge. A study now finds that Vδ1+ γδ T cells are associated with better response to ICB in melanoma tumors with a lower neoantigen load and shows that some effector functions of PD-1+ Vδ1+ T cells are repressed after engagement of PD-1 by PD-L1.

    • Hans R. Widlund
    • Lydia Lynch
    News & Views
  • Low-grade glioma is a tumor type that affects the central nervous system, with favorable survival outcomes in children and adolescents. A study now provides insights into long-term mortality and morbidity associated with different treatments and demonstrates the multifaceted outcomes of adult survivors of childhood glioma.

    • Johannes Gojo
    • Matthias Preusser
    News & Views
  • A genome-wide study of variation in mutation rates in human cancer reveals robust patterns of change in mutation risk across chromosomal domains and with varying replication times.

    • Xiaoju Hu
    • Subhajyoti De
    News & Views
  • Autotaxin (ATX) produces lysophosphatidic acid (LPA), which directly promotes pancreatic ductal adenocarcinoma (PDAC) growth, but the role of the tumor microenvironment (TME) in ATX-driven tumor growth is unclear. ATX–LPA signaling in PDAC is now shown to shape the TME by inhibiting eosinophil recruitment, resulting in increased tumor growth.

    • Sharon Grisaru-Tal
    • Ariel Munitz
    News & Views
  • Self-renewing cancer stem cells drive tumor initiation and progression and represent a major target for therapeutic development. A study now shows that vanoxerine, a dopamine transporter antagonist, precisely inhibits this cell population in colorectal cancer, which leads to attenuation of tumor initiation and increased infiltration by immune cells.

    • Winnie Chen
    • Ian Maze
    News & Views
  • Inhibiting glutamine metabolism has thus far been clinically challenging. Two studies in preclinical mouse models now report that, in contrast to the failure of glutaminase inhibitors, broad suppression of glutamine metabolism with glutamine analogs delivered to tumors results in reduced pancreatic cancer growth, with targetable resistance mechanisms.

    • Nada Y. Kalaany
    News & Views
  • Cancer cells seed distant tissues and remain dormant before re-entering the cell cycle to form metastases. How tumor dormancy is maintained and how cells exit dormancy is poorly understood. A study shows that the lncRNA MALAT1 reactivates dormant cancer cells by upregulating serpin protease inhibitors in tumor cells to evade CD8+ T cells.

    • Zhibin Zhang
    • Judy Lieberman
    News & Views
  • In vitro-transcribed RNA is a promising emerging class of therapeutic, but the poor specificity of cargo RNAs so far has limited their application in cancer immunotherapy. A new study reports the delivery of a synthetic circular RNA with inline cis-acting translational elements — encoding an engineered, mitochondrion-specific oncolytic protein — that shows both therapeutic and prophylactic potential against adenocarcinoma.

    • Alex G. Hamilton
    • Michael J. Mitchell
    News & Views
  • Transmissible cancer affects marine bivalve mollusks worldwide, but how genetic mechanisms influence cancer evolution and disease spread remains largely unexplored. Two new studies provide insights into the ancient origin of founder clones and the long-term tolerance of contagious cancer cells to extreme genome instability.

    • Anna Schönbichler
    • Andreas Bergthaler
    News & Views
  • Chimeric antigen receptor T cells and T cell-redirecting bispecific antibody therapies are changing the landscape of myeloma therapy. Two studies investigate the genetic and epigenetic resistance mechanisms that lead to relapse in patients receiving T cell-engaging therapies targeting B cell maturation antigen (BCMA) and GPRC5D.

    • Bruno Paiva
    • Jesús F. San-Miguel
    News & Views