Reviews & Analysis

Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.

A CRISPR dropout screen for tRNA regulators identified YRDC as the top essential gene in glioblastoma stem cells. Threonine acts as a substrate of YRDC to facilitate the N⁶-threonylcarbamoyladenosine (t⁶A) tRNA modification and shift translation toward mitosis-related genes with a codon bias. Our findings support targeting glioblastoma growth by a well-tolerated dietary therapy.

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.

Papagiannakopoulos and colleagues discuss the roles of reactive oxygen species in cancer and the ways in which redox mechanisms may be exploited for cancer therapy.

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.

Pancreatic cancer liver metastases show high levels of immunosuppressive macrophages, which promote tumor growth. We found that blocking the efferocytosis pathway during early-stage metastasis in a mouse model inhibited the development of immunosuppressive activity in monocyte-derived macrophages, which restored T cell activation and reduced the metastatic tumor burden.

Suijkerbuijk et al. summarize the clinical manifestation and classification of immune-related adverse events, discuss the immunopathogenesis of immune-related adverse events and provide key insights into their management and future therapeutic directions.

Our study reveals that the LGR4–Wnt signaling pathway dictates both ferroptosis and stemness traits to confer drug resistance to tumor cells. We thus generated a monoclonal antibody against LGR4 that blocks LGR4–Wnt signaling and sensitizes chemotherapy-resistant colorectal cancer tumors via selective promotion of ferroptosis.

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.

Using CRISPR–Cas9 screens, we found that cancer-cell-intrinsic loss of Pip4k2c conferred liver-metastatic organotropism in melanoma through hypersensitization to insulin-mediated PI3K–AKT signaling via co-optation of distinct hepatic metabolic cues. Additionally, we showed that combinatorial therapies that abolished physiological and drug-induced changes in glucose and insulin levels specifically reduced liver metastasis.

Mitochondrial DNA mutations are present in over 50% of all cancers, and truncating mutations in several genes encoding components of complex I of the respiratory chain are most recurrent. We found that these mutations are a source of Warburg-like metabolic shifts that promote a pro-inflammatory immunological state, enhancing sensitivity to checkpoint blockade.

Senescent cancer cells, which are characteristically present in tumors after genotoxic therapies, upregulate the immune checkpoint ligand programmed cell death 1 ligand 2 (PD-L2). We show that genetic or pharmacological ablation of PD-L2 prevents the accumulation of intratumoral senescent cells, reducing the recruitment of immunosuppressive myeloid cells and facilitating tumor clearance by T cells.

Imetelstat is a first-in-class telomerase inhibitor with efficacy in a number of blood cancers. Intriguingly, telomere lengths do not predict patient responses to imetelstat. We now show that imetelstat causes cell death by a mechanism that involves two regulators of fatty acid metabolism (FADS2 and ACSL4), driving excessive lipid reactive oxygen species formation and ferroptosis.

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.

Van Loo and colleagues review the mechanistic underpinnings of large genomic alterations and their roles in tumor development and evolution.

We applied an artificial intelligence (AI) approach to a dataset of clinical and advanced multi-omic molecular features from patients with pancreatic adenocarcinoma to predict survival. The results reveal a tumor-type-agnostic platform that can identify parsimonious and robust clinical prediction biomarkers, catalyzing the vision to democratize precision oncology worldwide.