Robinson et al. challenge the reliance on neurosurgery for glioma diagnosis by integrating multi-omic profiling of plasma extracellular vesicles with machine learning. Across independent cohorts, these biomarkers discriminate between glioma and controls and enable longitudinal tracking of tumor burden, establishing a clinically relevant foundation for minimally invasive diagnosis, monitoring, and stratification.
Nonclassical major histocompatibility complex class I (MHC-I) molecules, including human leukocyte antigen E (HLA-E), HLA-F, HLA-G, MHC-I-related protein 1 (MR1), and the CD1 family, constitute a conserved antigen-presenting system that regulates immune surveillance, tissue homeostasis, and tolerance through specialized interactions with innate and unconventional T cells. Although these molecules have long been implicated in cancer, infection, autoimmunity, and transplantation, their distinct immunobiology and therapeutic potential have largely been considered in isolation. Recent advances in structural immunology, single-cell and spatial profiling, engineered immune cell technologies, and early clinical studies have established nonclassical MHC-I pathways as tractable targets for immunotherapy. In this review, we synthesize the biology, disease-associated functions, and therapeutic targeting of these molecules, integrating immune checkpoint blockade, antibody-based therapeutics, and MR1- and CD1-restricted cellular immunotherapies into a unified framework. We further highlight shared immunological principles, emerging clinical translation, and opportunities for universal, off-the-shelf immune interventions.
Cancer cachexia has long been attributed to circulating factors. Cross et al. now show that, in liver kinase B1 (Lkb1)-mutant lung tumors, local prostaglandin E2 acts on vagal neurons to drive anorexia and wasting, accelerated by fat. Defining metaboception as neural sensing of local signals-a new therapeutic concept.
Skeletal development, maintenance, and repair require precise control of protein production, yet mRNA levels often correlate poorly with protein abundance. Translation is the process through which mRNA is converted into protein, but its role in skeletal biology remains much less understood than that of transcriptional regulation. Recent advances in translatomics have begun to reveal how translational regulation contributes to skeletal development, homeostasis, and repair. Here, we summarize translational control across skeletal lineages, developmental stages, and disease settings. We also discuss emerging approaches for studying mRNA translation and potential therapeutic opportunities that target translational pathways. Understanding how translational regulation shapes skeletal health and disease will open new avenues for precise interventions for skeletal defects.
The unclear regulatory and transport mechanisms of Kirsten rat sarcoma viral oncogene homolog (KRAS) limit a comprehensive understanding of KRAS activity and the development of inhibitors. Wang et al. reported that farnesylation-induced KRAS phase separation drives colon cancer progression and resistance to G12C inhibitors. Statins can block this process, suppress tumor growth, and reverse drug resistance.
Fungal infections cause millions of deaths, yet clinical antifungals span only three drug classes. Koch et al. discover formicitoxins-35 venom peptides from carpenter ants-which are the first from any formicine species. Two outperform voriconazole in vitro and delay infection in vivo. Formicitoxins disrupt fungal membranes independently of existing drug targets.
Early lung tumorigenesis depends not only on mutant clones but also on tumor-promoting niches that remain difficult to detect. In Cell, Pandya et al. identify a 14-protein plasma signature that predicts lung cancer years before diagnosis, report interleukin-1β-linked alveolar remodeling, and position tumor promotion as a target for precision prevention.
Interindividual variability in response to cancer therapy is a major challenge in the management of colorectal cancer (CRC). The gut microbiome contributes to differential therapeutic efficacy and toxicity by modifying the pharmacokinetics and pharmacodynamics of anticancer drugs. Furthermore, bacterial products interact with tumor and immune cells, altering therapeutic outcomes. This review focuses on the impact of pharmacomicrobiomics on CRC therapy. We describe how gut microbiota affects drug metabolism on a mechanistic level and outline the interactions of specific microbes and their products with chemo-, targeted, and immunotherapies employed in CRC. Finally, we provide an overview of current strategies, including probiotics, engineered bacteria, and fecal microbiota transplantation, that exploit the gut microbiome to improve therapeutic efficacy and reduce toxicity.
Ferroptosis has emerged as a critical contributor to secondary brain injury in cerebrovascular diseases (CVDs). However, the clinical translation of antiferroptotic therapies remains stalled because current strategies often treat CVDs as a uniform entity, neglecting profound pathophysiological heterogeneity. In this review, we propose a pathology-guided framework mapping distinct ferroptotic cascades across CVDs. We delineate how ischemic stroke hinges on endogenous iron retention and the collapse of nuclear factor erythroid 2-related factor 2 antioxidant defenses, whereas hemorrhagic stroke is triggered by acute exogenous heme influx. Furthermore, chronic hypoperfusion in vascular dementia lowers the threshold for oligodendrocyte ferroptosis. By deconstructing these subtype-specific mechanisms-from iron overload modes to lipid vulnerability-we emphasize a paradigm shift for CVD: advancing precision medicine requires mechanism-stratified, context-dependent interventions rather than uniform ferroptosis inhibition.
Horizontal mitochondrial transfer (HMT) outcomes are shaped by donor fitness and transfer context. We propose a post-transfer quality checkpoint that integrates membrane potential, oxidative damage, mitophagy, fusion, and fission to determine the recipient-cell's response. Depending on donor quality and recipient thresholds, HMT may drive bioenergetic restoration, inflammation, or tumor immune escape. This framework extends route-centered accounts of HMT toward a testable, quality-governed model for therapeutic intervention.
A recent study by Cohen et al. identified stress-induced keratin 16 (KRT16) as an active regulator of skin innate immunity. By sequestering 14-3-3ε, KRT16 suppresses retinoic acid-inducible gene I-mediated type I interferon (IFN) signalling. KRT16 loss in pachyonychia congenita amplifies inflammatory IFN signalling, highlighting the KRT16-IFN signalling axis as a potential therapeutic target.
The nucleolus is a master regulator of ribosome biogenesis and cellular homeostasis, as well as an increasingly key determinant of neuromuscular diseases. Across these conditions, diverse genetic and molecular lesions converge on alterations in nucleolar organization and function. These changes impact ribosomal RNA synthesis and reshape translational output, linking nuclear events to cytoplasmic protein homeostasis in disease-relevant contexts. In this review, we propose a comprehensive framework in which the nucleolus integrates RNA dysfunction, genome organization, and translational control across neuromuscular disorders. This perspective provides a conceptual basis for interpreting disease heterogeneity and highlights nucleolar pathways as potential, underexploited targets for therapeutic intervention.
Ferroptosis is a unique form of programmed cell death that involves multiple organelles. Although traditionally viewed as a 'degradation workshop', accumulating evidence reveals that the lysosome serves as a central hub for iron metabolism and signal transduction, orchestrating the overall fate of cellular ferroptosis across spatiotemporal dimensions. In this review, we propose the concept of the 'lysosome-ferroptosis axis' and outline its roles in metabolic signaling, autophagy, and lysosomal membrane permeabilization. We further discuss the involvement of this axis in neurodegenerative, tumor, and cardiometabolic diseases, with the aim of providing new insights for targeted therapeutic strategies.
Disorders involving endosomal signaling pathways are gaining attention due to their roles in immune regulation. This review proposes a new disease category, endosomal signaling disorders (ESDs), to describe disorders caused by dysfunction of endosomal molecules. Dysregulated endosomal signaling leads to hyperactivation of immune responses, contributing to immune dysregulation disorders such as systemic lupus erythematosus and systemic autoinflammatory disorders. The identification of pathogenic variants in endosomal genes such as TLR3, TLR7, TLR8, UNC93B1, and PLD4 emphasizes the importance of endosomal dysfunction in the pathogenesis of immune dysregulation disorders. Categorizing these diseases as ESDs can help better diagnose and treat these complex conditions, paving the way for targeted therapies and improved patient outcomes.
Deubiquitinases regulate key oncogenic and immune pathways but have proven challenging to exploit therapeutically. Among them, ubiquitin-specific protease 22 (USP22) has emerged as a molecule of interest due to its involvement in both tumor-intrinsic programs and tumor-immune interactions. In this review, we synthesize current evidence describing how USP22 modulates oncogenic transcriptional states and immune evasion. Tumor-intrinsically, USP22 has been implicated in stabilizing select oncogenic factors and shaping chromatin accessibility in ways that can reinforce proliferation, survival, stem-like properties, and metastatic potential. In parallel, USP22 influences antitumor immunity by modulating MHC-I-mediated antigen presentation, immune checkpoint expression, and the fitness of intratumoral regulatory T cells. We discuss emerging pharmacological approaches to target USP22, the limitations of current inhibitor strategies, and the importance of distinguishing direct enzymatic functions from indirect transcriptional consequences. Together, these insights suggest that USP22 inhibition may offer a therapeutic strategy with dual effects on tumor biology and antitumor immunity.
Neuroimmune circuits are emerging as a critical layer of host defense. Recent studies show that sensory neurons shape interferon responses, myeloid dynamics, and T cell priming during viral infection, while viruses reprogram these circuits to drive immune pathology. These findings define a dynamic neuro-virus-immune axis with important therapeutic implications.
Hyocholic acids (HCAs), synthesized by fetal CYP3A7, dominate the neonatal bile acid pool. By promoting regulatory T cells and suppressing T helper 17 cells, HCAs establish intestinal immune tolerance, guide healthy microbiota assembly, and protect infants from infections and gastrointestinal disorders (Zheng et al.).
Clonal hematopoiesis is emerging as a surprising modifier of Alzheimer's disease. Recent findings suggest that mutant myeloid cells may enter or expand within the brain, adopting either inflammatory or reparative states. We propose that their effects depend on the mutation, timing, clone size, brain niche, and disease stage.
Tumor progression depends on coordinated adaptation of cancer cells and the tumor microenvironment to immune pressure, metabolic limitations, genomic instability, and biomechanical stress. While these adaptive responses have often been investigated through distinct experimental and conceptual frameworks, increasing evidence indicates that they converge on shared regulatory pathways. Calcium signaling is a fundamental regulator of cellular adaptation; however, its role in integrating tumor stress responses remains unclear. This review synthesizes emerging evidence identifying calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) as a key regulator linking calcium signaling to coordinated tumor and microenvironmental adaptation across mechanical, metabolic, replication, and immune stress responses. We discuss how CaMKK2 supports tumor ecosystem fitness through convergent tumor-intrinsic and microenvironmental programs and consider the therapeutic implications of targeting CaMKK2 and its signaling network, emphasizing context dependence, rational combination strategies, and biomarker-guided clinical translation.
