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  • 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
  • Certain cancers disrupt metabolism, leading to the wasting syndrome known as cachexia. How tumor-induced mediators of cachexia induce changes in end organs is unclear. A study implicates the endothelium as an amplifier of tumor signals in fat, in which NOTCH1 promotes adipose tissue remodeling via retinoic acid, IL-33 and IGFBP3.

    • Brittany R. Counts
    • Teresa A. Zimmers
    News & Views
  • The nervous system regulates cancer progression, and the importance of neuron–glioma communication in tumor growth is evident in glioblastoma. This tumor-promoting communication presents a potential therapeutic axis, a concept reinforced by a study that identifies a specific potassium channel complex as a therapeutic target.

    • Stephen M. Robbins
    • Donna L. Senger
    News & Views
  • The development of immunotherapies for acute myeloid leukemia (AML) has been limited by a lack of known tumor-specific targets. A study now shows the feasibility of developing highly sensitive and selective T cell-receptor-based therapies against an HLA-A*02:01-associated peptide derived from a recurrent mutation in a subset of patients with AML.

    • Anca Apavaloaei
    • Claude Perreault
    News & Views
  • The recent design of mutation-selective KRAS inhibitors has led to US Food and Drug Administration approval of two inhibitors of KRAS(G12C), sotorasib and adagrasib. A study published in Nature reports the development of a first-in-class pan-KRAS-selective inhibitor. Here we comment on the current status of KRAS-targeting approaches.

    • Ryan B. Corcoran
    News & Views
  • The advantage of genomic monitoring over cytogenetics for clinical assessment of leukemia is illustrated by a case of pediatric acute lymphoblastic leukemia in which a lesion underlying lethal end-stage myeloid disease could be detected by whole-genome sequencing years before the risk manifested cytogenetically.

    • Lauren M. Harmon
    • Timothy J. Triche Jr
    News & Views
  • CD8+ T cells recognize tumor-associated antigens presented by major histocompatibility complex (MHC) class I molecules. How CD8+ T cells eliminate cancer cells deficient in MHC class I has been unclear. A study now shows that adaptive CD8+ T cell activation induces expression of the innate receptor NKG2D for the elimination of MHC class I–deficient tumors.

    • Christopher E. Rudd
    News & Views
  • Glioblastoma is an aggressive brain tumor with a highly immunosuppressive environment that responds poorly to immune checkpoint inhibitors. A study shows that SIGLEC9+ monocyte-derived macrophages are enriched in glioblastomas that do not respond to immune checkpoint inhibitors, and targeting this receptor synergizes with immunotherapy.

    • Thomas U. Marron
    • Jennifer L. Guerriero
    News & Views
  • Pathological diagnosis relies on morphological assessment of tissue using histological staining and molecular phenotyping through immunostaining that must be performed on separate tissue sections. Orion is a newly reported methodology that facilitates multiplexed immunostaining with histological staining on the same slide.

    • Ashley N. Anderson
    • Summer L. Gibbs
    News & Views
  • Distinct subsets of γδ T cells that operate to either prevent or promote cancer progression have been characterized in mice. A study now indicates that human tumor-infiltrating γδ T cells also are more diverse than previously appreciated, consisting of functionally distinct subsets with tumor-promoting or -restricting functions.

    • Seth B. Coffelt
    • Toshiyasu Suzuki
    News & Views