News & Views

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.

Brain tumors are challenging to diagnose, with DNA-methylation profiling being key to their classification, but with AI-based classifiers requiring constant adjusting to newer technologies. A publicly available AI tool is now shown to classify tumors with high accuracy, independently of profiling platform, epigenome coverage or sequencing depth.

Cancer cells form stress granules that enable them to adapt to stress and survive. Research now shows that after drug treatment, hepatocellular carcinoma cells display phase separation mediated by the RIOK1 kinase, which promotes sequestration of PTEN mRNA in stress granules. This activates the pentose phosphate pathway, favoring cell survival.

The complex nature of metastasis-initiating cells (MICs) has long hindered our understanding of how cancer spreads and how to prevent it. A study now identifies a potential MIC population and a crucial role for extracellular vesicles in the immune-evasion tactics of these cells.

CHD1 loss is common in SPOP-mutant prostate cancer; however, this combined phenotype has not yet been clearly defined. Genetically engineered mouse models of prostate cancer with Chd1 loss and Spop mutation now reveal a mechanism of castration resistance driven by enhanced intracellular cholesterol and androgen biosynthesis.

Personalized neoantigen vaccines utilize mutation-driven neoantigens to induce tumor-specific immune responses. This strategy is now shown to be feasible and safe, with preliminary evidence of efficacy and immunogenicity in patients with urothelial cancer or renal-cell carcinoma.

Comprehensive understanding of the molecular mechanisms that underlie ferroptosis is essential for the development of new anti-tumor therapies. Palmitoylation of GPX4 is now shown to increase its stability and change its cellular localization and thus promote resistance to ferroptosis in cancer.

Delta One T (DOT) cells are primarily Vδ1⁺ γδ T cells with strong cytotoxic activity, now in clinical studies for the treatment of leukemias but not yet evaluated in solid cancers. Adoptive transfer of DOT cells combined with butyrate or checkpoint inhibitors is now shown to be an effective therapy for colorectal cancer in preclinical models.

Chimeric antigen receptor (CAR) macrophage therapy has shown promising activity in preclinical models of solid tumors. A platform that combines CAR technology with lipid nanoparticles for in vivo macrophage engineering is now shown to generate pro-inflammatory CAR macrophages with sustained tumoricidal activity as effective therapy against renal cell carcinoma.