Reviews & Analysis

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.