News & Views

Applications of digital pathology in clinical oncology have largely depended on the requirement for labeled data and model re-training. A study now presents PRET, a training-free framework with robust performance for pan-cancer diagnosis that adapts pathology foundation models to diverse tasks at inference stage, from screening and subtyping tasks to segmentation and metastasis detection tasks.

Leptomeningeal metastases are a devastating complication of solid tumors; how this niche becomes pro-metastatic remains poorly understood. A study now reveals that tumor cells prime a pre-metastatic niche within the leptomeninges via exosome-derived 5-HIAA, triggering vascular leakiness and accumulation of disseminated tumor cells.

Cerebrospinal fluid (CSF)-derived cell-free DNA holds promise for CNS tumors, but its limited yield poses challenges. A study now presents M-PACT, a framework that uses sub-nanogram CSF-derived cell-free DNA methylomes for tumor classification, paving the way for minimally invasive diagnosis of pediatric brain tumors.

RNA N⁶-methyladenosine (m⁶A) is the most abundant internal RNA modification, yet its functional landscape in cancer remains poorly defined. A study now introduces a METTL3-based RNA base-editing screen that maps functional m⁶A sites and reveals m⁶A-dependent translational activation of the tumor suppressor CHD9 in prostate cancer and beyond.

Whether support from artificial intelligence (AI) models improves breast screening is a topic of research in national cancer screening programmes and clinical oncology. Three studies now show that AI tools can assist radiologists with evaluating mammograms, substantially reducing workloads and possibly improving screening performance.

Strategies are needed to overcome resistance to immune checkpoint inhibitors in patients with cancer. An erythrocyte–antibody conjugate for the delivery of anti-PD-1 is now shown to favorably reshape anti-tumor immune responses, with promising safety and efficacy data from a phase 1 trial in patients with advanced anti-PD-1-resistant solid tumors.

Dynamic cellular changes within the tumor immune microenvironment inform clinical responses. Two studies now present automated tools that analyze complex spatial patterns to discern prognostic spatial features of triple-negative breast cancer specific to cell interactions at the tumor border or metastatic site.

Desmoplastic melanoma, a rare form of skin cancer, is characterized by a high tumor mutational burden and is likely to benefit from treatment with immune checkpoint inhibitors. Results from a phase 2 clinical trial now suggest the efficacy of single-agent PD-1 blockade in the treatment of both resectable and unresectable desmoplastic melanoma.

Methods to increase HER2 expression in breast cancer could expand the population eligible for treatment with trastuzumab deruxtecan (T-DXd), a HER2-directed antibody–drug conjugate. A study now reports that the membrane-bound E3 ligase FBXL2 regulates degradation of HER2, and FBXL2 inhibition sensitizes HER2-negative breast cancer cells to T-DXd.

Activation of cytosolic nucleic acid sensors in tumor cells is an important early step for initiating antitumor immunity, but the mechanisms controlling their activity are not fully understood. Using an in vivo CRISPR screen, CDK10 is now revealed as a cancer cell-intrinsic driver of immune evasion that limits production of immunostimulatory nucleic acids.

Dormant metastases can lead to tumor relapse after many years by successfully escaping immune surveillance. A new study identifies an atypical epithelial-to-mesenchymal transition state that presents low stiffness mediated by actin depolymerization, which prevents immune cell-mediated killing of dormant metastatic lung adenocarcinoma.

Tumor-infiltrating microorganisms have been presented as an unappreciated component of the tumor microenvironment, but there are few examples of their influence on tumor phenotypes or response to therapies. The total amount of bacteria is now shown to influence immunotherapy outcomes in head and neck squamous cell carcinoma.

RAS–MAPK pathway inhibitors are limited by pathway reactivation and toxicity. A study now introduces IK-595, a MEK–RAF molecular glue that stabilizes MEK in an inactive complex with RAF isoforms, enabling durable inhibition of ERK signaling and anti-tumor activity in various cancers in which RAS or RAF is altered, including those resistant to current standard-of-care therapies.

Little is known about how mutations in genes encoding tumor suppressors influence metastatic site selection and whether sustained inactivation of such genes influences tumor maintenance at these sites. A new study shows that restoration of Smad4 expression in extant pancreatic metastases has anti-tumor effects in the liver but pro-tumor effects in the lungs.

Prostate MRI has emerged as a way to improve accuracy in prostate cancer diagnostics. However, the subjectivity of assessments remains a challenge. New research shows that AI can help in this task and serve as a tool to improve MRI-based prediction of prostate cancer aggressiveness.

Cancer-associated fibroblasts represent a functionally diverse and heterogeneous entity within the solid tumor microenvironment. Mitochondrial transfer from cancer cells to fibroblasts is now shown to act as a reprogramming stimulus, driving metabolic and functional differentiation of fibroblasts to support tumor growth.

Glioblastoma (GBM) is highly invasive, but the crosstalk between GBM cells and glia at the invasion front is unclear. A study now analyzes the invasive region and shows that GBM cells induce plexin-B2 expression in macrophages and microglia to guide extracellular matrix remodeling and facilitate a shift from bulk to infiltrative GBM growth.

Muscle atrophy in cachexia drives weight loss and represents a major complication for patients with cancer. The tumor-derived cytokine activin A is now shown to decrease endothelial cell viability in skeletal muscle, leading to loss of muscle mass and function and inducing cachexia in multiple preclinical cancer models.

B cell leukemias are heterogeneous cancers believed to develop from pro-B lymphoid progenitors. Single-cell transcriptomics of patients and donors now reveal a map of B cell leukemia cell states and suggest that the cell of origin may be more dedifferentiated than previously assumed, thus influencing our understanding of the disease.

The short lifespan and systemic toxicity of IL-2 are major limitations for IL-2-based cancer immunotherapy. To overcome these hurdles, a single dose of a pressure-fused biomineral tablet is shown to safely support a two-phase IL-2 release, leading to weeks-long intratumoral retention of the cytokine to promote anti-tumor T cell immunity.