The case for treating large extracellular vesicles as their own category rests on a fundamental difference in origin. Small extracellular vesicles arise from two well-characterised sources: the endosomal system, which produces exosomes when multivesicular bodies fuse with the plasma membrane, and the plasma membrane itself, which buds off small ectosomes. Most large extracellular vesicles, by contrast, stem directly from the plasma membrane, although the review emphasises that the various subtypes follow strikingly different biogenesis routes. This distinction matters because it shapes what the vesicles carry, how they are released, and what they do once they arrive at a recipient cell. A vesicle born from a dying cell’s collapsing membrane carries a very different cargo than one pinched off from the rear of a migrating cell or extruded from a neuron under proteotoxic stress.

The classical cast of large vesicles includes apoptotic bodies, microvesicles and large oncosomes, each recognised for years and each associated with distinct biology. Apoptotic bodies form as dying cells disassemble themselves, a process driven by caspase-mediated activation of ROCK1, which triggers the actomyosin contraction underlying membrane blebbing. These fragments are far more than debris: they broadcast find-me and eat-me signals that orchestrate the orderly clearance of dead cells by phagocytes, and recent work shows they can stimulate stem cell proliferation during tissue maintenance and couple bone resorption to bone formation. Microvesicles, shed directly from the plasma membrane of viable cells, depend on the ARF6–myosin light chain–actomyosin axis for their scission, and tumour cells exploit this pathway to spread oncogenic receptors such as EGFRvIII and drug-resistance proteins like P-glycoprotein to neighbouring cells. Large oncosomes, the giant vesicles shed by cancer cells, have been linked to loss of the formin DIAPH3 and to the reprogramming of fibroblasts in the tumour microenvironment through MYC-dependent mechanisms.

The most exciting chapters of the review concern the newer subtypes, several of which were unknown when the extracellular vesicle field consolidated its nomenclature under the MISEV guidelines. Migrasomes, discovered in 2015 by Li Yu’s group, form on retraction fibres left behind by migrating cells and serve as organelles for controlled release of cytoplasmic contents during cell migration. Their formation depends on the assembly of micron-scale tetraspanin-enriched macrodomains, driven by sphingomyelin synthase 2, phosphatidylinositol 4,5-bisphosphate signalling through Rab35, and palmitoylation of the tetraspanin Tspan4. Migrasomes have since been implicated in zebrafish organ morphogenesis, embryonic angiogenesis, mitochondrial quality control through a process termed mitocytosis, and even coagulation, with neutrophil-derived migrasomes identified as essential components of the clotting system.

Equally remarkable are the vesicles that cells use to jettison damaged components. Exophers, first described in Caenorhabditis elegans neurons in 2017, are enormous vesicles through which stressed neurons extrude toxic protein aggregates and dysfunctional mitochondria, providing a proteostasis escape route with obvious implications for neurodegenerative disease. Mitophers, reported in 2023, represent a form of mitochondria-specific ectocytosis through which sperm cells regulate their mitochondrial complement and, consequently, their fertility, establishing a paradigm for cargo-selective packaging of entire organelles into large vesicles. Blebbisomes, characterised in 2025, are large, organelle-rich vesicles with startling cell-like properties, carrying broad organellar cargo and expanding the functional repertoire attributed to vesicle-mediated communication. Large ageing neutrophil-derived vesicles, or LAND-Vs, add an anti-inflammatory dimension: they control complement activation and facilitate the resolution of inflammation, revealing that large vesicles can dampen immune responses as well as provoke them.

Beneath this diversity lies a set of shared physical and biochemical principles that the review dissects with technical precision. Membrane budding and scission require the coordination of actomyosin contractility, hydrostatic pressure and lipid remodelling. The transbilayer distribution of phospholipids emerges as a recurring regulatory node: flippases maintain lipid asymmetry, while scramblases such as TMEM16F collapse it in a calcium-dependent manner, exposing phosphatidylserine on the outer leaflet and promoting both vesicle release and the engulfment signals that mark apoptotic material for clearance. Disruption of flippase localisation in C. elegans increases extracellular vesicle budding, demonstrating that lipid asymmetry actively suppresses vesiculation in healthy membranes. Protein crowding at the membrane, tetraspanin microdomains, lipid rafts and caveolin-dependent dynamics each contribute to curvature generation at specific sites, while the ESCRT machinery contributes its membrane-scission capabilities to several of these pathways.

Cargo sorting into large vesicles follows equally mechanistic rules. The ARF6–Exportin-5 axis delivers pre-microRNA cargo into tumour microvesicles, Cdc42 acts as a regulatory node for microvesicle biogenesis, and RNA-binding proteins govern which transcripts are packaged. Zipcode-like sequence elements enrich specific mRNAs in microvesicles, and integrin pairing with extracellular matrix proteins determines where migrasomes form on retraction fibres. Delivery to recipient cells proceeds through clathrin-independent endocytosis and macropinocytosis, although the review is careful to note that the field still lacks definitive experimental support for functional cargo transfer in many contexts, a caution that reflects growing scrutiny of the extracellular vesicle cargo-transfer hypothesis.

The pathological implications are broad and, in several cases, already translating toward clinical applications. In cancer, large vesicles transfer oncogenic receptors, promote angiogenesis through CD147 and VEGF signalling, carry retrotransposon elements and amplified oncogene sequences, and mediate immune evasion through vesicle-associated PD-L1, which Epstein–Barr virus LMP1 enhances. In neurodegeneration, microglia convert aggregated amyloid-beta into neurotoxic forms through microvesicle shedding, while macrophage-derived migrasomes activate complement-dependent blood–brain barrier damage in cerebral amyloid angiopathy and promote paracrine senescence in ageing brain. Inflammation, thrombosis and kidney injury each feature large-vesicle mechanisms, with urinary podocyte-derived migrasomes emerging as early indicators of glomerular damage and plasma apoptotic bodies serving as non-invasive biomarkers of apoptosis in ischemic stroke.

Methodological rigour occupies a central place in the review’s argument. The authors catalogue the technologies now enabling multidimensional characterisation, from cryo-electron microscopy and super-resolution structured illumination microscopy to nanoparticle tracking analysis, tunable resistive pulse sensing, asymmetric flow field-flow fractionation and microfluidic affinity capture. Deep-learning platforms for automated detection of vesicle exocytosis and self-supervised image enhancement for long-term subcellular recording are extending what live imaging can reveal. Yet the review is equally candid about pitfalls: fluorescent lipophilic dyes can confound uptake studies, isolation methods such as ultracentrifugation and tangential flow filtration yield different preparations, and loss-of-function studies and mechanistic analyses must be appropriately integrated to ensure rigour and reproducibility. Engineered migrasomes that serve as thermally stable vaccination platforms hint at the therapeutic horizon, but the authors stress that biodistribution depends on cell source, administration route and targeting ligands, and that the field’s progress will depend on pairing new tools with the disciplined standards set out in the MISEV2023 framework. What emerges is a portrait of a maturing discipline: one in which the largest and most structurally complex members of the extracellular vesicle family are finally being studied with the systematic attention their biology demands.

Subject of Research: Subtypes, biogenesis and functions of large extracellular vesicles

Article Title: Towards a systematic understanding of the diverse subtypes, biogenesis and functions of large extracellular vesicles

Article References: Huang, Y., Xie, R., Ma, J., & Yu, L. (2026). Towards a systematic understanding of the diverse subtypes, biogenesis and functions of large extracellular vesicles. Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-026-01021-8

Image Credits: AI Generated

DOI: 10.1038/s41580-026-01021-8

Keywords: large extracellular vesicles, migrasomes, apoptotic bodies, microvesicles, large oncosomes, exophers, blebbisomes, mitophers, plasma membrane budding, tetraspanins, extracellular vesicle biogenesis, cell-cell communication

Migrasomes are a relatively recently characterized organelle. First described as large vesicles that form on the long retraction fibers left behind when a migrating cell pulls itself forward, they accumulate cellular contents before being released or taken up by neighboring cells. The new study demonstrates that circulating tumor cells, as they squeeze through vascular channels and navigate the demanding physical environment of the bloodstream, produce migrasomes loaded with tumor-derived antigens. This finding reframes migrasomes from a curiosity of cell biology into a consequential player in cancer immunology, one that links the mechanical act of tumor cell migration to the triggering of adaptive immune responses.

The central immunological mechanism at work in the study is cross-presentation, the specialized ability of certain antigen-presenting cells, most notably dendritic cells, to display fragments of extracellular proteins on MHC class I molecules. This pathway is essential because cytotoxic CD8-positive T cells can only recognize antigens presented in this manner. When dendritic cells engulf the antigen-bearing migrasomes shed by circulating tumor cells, they process the tumor proteins and present peptide fragments on their surface, effectively showing the immune system a wanted poster of the metastasizing cancer. Naive CD8-positive T cells that recognize these fragments can then expand into armed effector cells capable of seeking out and killing tumor cells that display the same antigens.

What makes the discovery especially striking is its paradoxical framing: metastasis itself enables immunogenicity. The very traits that allow tumor cells to disseminate, including their motility, their deformation through narrow vessels, and their production of retraction fibers and migrasomes, simultaneously generate the antigen-release route that exposes them to immune surveillance. In this sense, the metastatic phenotype carries an intrinsic cost. A tumor cell that migrates aggressively through the circulation sheds more migrasomes, and by doing so provides more antigen for dendritic cells to capture and present. The authors show that this antigen release can activate CD8-positive T cells, and that the resulting T cell response acts to restrict metastasis rather than facilitate it.

From a technical standpoint, the study implies that migrasome shedding constitutes a previously underappreciated antigen source in the metastatic setting. Traditional models of tumor antigen release have emphasized cell death, with necrotic or apoptotic tumor cells spilling their contents, and secretion of soluble proteins or exosomes. Migrasomes add a distinct route: antigen export coupled directly to live cell migration. Because the migrasomes form on retraction fibers during active locomotion, this antigen release does not require tumor cell death and may therefore occur continuously and at low levels during the earliest phases of dissemination, potentially priming the immune system before a metastatic colony becomes established.

The engagement of CD8-positive T cells through cross-presentation is significant for cancer immunotherapy. Modern approaches such as immune checkpoint inhibitors and therapeutic cancer vaccines depend on the existence of pre-existing or inducible T cell responses against tumor antigens. If migrasome-mediated antigen release contributes to natural priming of anti-tumor T cells, then the efficiency of this process could influence which patients respond to immunotherapy. Tumors or microenvironments that suppress migrasome formation, interfere with dendritic cell uptake, or block cross-presentation might evade immune detection even while shedding antigen. Conversely, therapies that enhance migrasome production or improve cross-presentation could strengthen endogenous anti-metastatic immunity.

The findings also carry implications for understanding metastatic tropism and relapse. Metastatic recurrence frequently emerges months or years after removal of a primary tumor, driven by disseminated tumor cells that linger in distant tissues. If migrasome-mediated antigen release can prime CD8-positive T cells capable of restricting metastasis, then the balance between migrasome-driven immune priming and immune evasion may help determine whether disseminated cells are eliminated or allowed to persist. Therapeutic strategies that tip this balance toward immunity, for example by vaccinating patients with antigens delivered in a migrasome-like format or by combining checkpoint blockade with agents that promote antigen cross-presentation, could in principle convert the metastatic process into a self-limiting event.

The study also broadens the emerging appreciation of extracellular vesicles as coordinators of immunity. Exosomes, microvesicles, and now migrasomes each carry distinct cargo and follow distinct biogenesis pathways, and their immunological consequences can be opposing: some vesicle populations suppress immunity while others, as shown here, promote T cell activation. Distinguishing these populations and understanding which vesicle types dominate in a given tumor context will be essential for designing interventions. The migrasome pathway, being tied to cell migration, is unusually amenable to modulation by factors that affect tumor cell motility, cytoskeletal dynamics, and vascular transit, offering multiple points of potential pharmacological control.

Looking forward, the work suggests several concrete research directions: quantifying migrasome shedding in patient blood samples as a biomarker of immune priming, mapping which dendritic cell subsets capture migrasomes most efficiently, and testing whether engineered migrasomes loaded with defined tumor antigens can serve as vaccines against metastasis. The image that emerges is one of a cancer cell caught in a biological dilemma. Movement is what makes metastasis lethal, but movement also forces the cell to leave behind membrane-bound fingerprints that the immune system can read. Harnessing that dilemma, the study suggests, may become a new frontier in the effort to stop cancer from spreading.

Subject of Research: Migrasome-mediated tumor antigen release during metastasis and its activation of CD8-positive T cell immunity

Article Title: Metastasis enables immunogenicity through migrasome-mediated antigen release

Article References: Jiang, D., He, J., Xie, R., Shi, M., Liu, S., Jia, H., Yang, B., Ruan, X., Tao, X., Xiang, Y., Chen, Y., Jiao, L., Feng, X., & Yu, L. (2026). Metastasis enables immunogenicity through migrasome-mediated antigen release. Nature Immunology. https://doi.org/10.1038/s41590-026-02641-0

Image Credits: AI Generated

DOI: 10.1038/s41590-026-02641-0

Keywords: metastasis, migrasomes, circulating tumor cells, tumor antigens, cross-presentation, CD8-positive T cells, Nature Immunology, cancer immunology, dendritic cells, extracellular vesicles, anti-tumor immunity, cancer immunotherapy

Migrasomes are membrane-bound vesicles that form behind cells as they migrate, leaving behind a trail of signaling packages that can influence neighboring cells. Although first characterized only in the last decade, these organelles have increasingly been implicated in cancer biology, where migrating tumor and stromal cells may use them to reshape their surroundings. What has remained murky, however, is precisely which cells in a tumor produce migrasomes, how they communicate with immune and structural cells, and whether migrasome activity carries clinically meaningful information about prognosis. The new study set out to answer those questions for gastric cancer, an aggressive disease characterized by dense and complex interactions between malignant cells and the surrounding tumor microenvironment.

The investigators began with single-cell RNA sequencing of fourteen gastric cancer specimens using the 10x Genomics platform. Unsupervised clustering resolved nine transcriptionally distinct cell clusters, which the team annotated into eight major cellular compartments spanning malignant epithelial cells, immune populations, and stromal cells. To quantify migrasome activity, the researchers scored each cell against a curated set of migrasome-associated genes. Fibroblasts stood out immediately: they displayed the highest migrasome scores of any compartment and also achieved the highest cell-type identification accuracy in the Augur computational framework, with an area under the curve of 0.805. This dual prominence suggested that fibroblasts are not merely present in gastric tumors but are the primary migrasome-producing population whose behavior changes across the disease landscape.

Digging deeper, the team identified eleven fibroblast-specific migrasome-associated genes, abbreviated FSMAGs, that defined this signature. Pseudotime trajectory analysis, which orders cells along a computational timeline of differentiation, revealed five distinct fibroblast differentiation states within the tumors. As fibroblasts progressed along this trajectory, the expression of the chemokine CXCL12 and the tetraspanin TSPAN4 rose steadily, while the related gene TSPAN9 remained comparatively stable across all states. The divergence of TSPAN4 from its family member hinted that it plays a specialized, state-dependent role rather than serving as a generic structural component, a hypothesis the researchers went on to test functionally.

Because tumors are communication hubs as much as collections of cells, the team used CellChat, a computational tool that infers ligand-receptor signaling between cell populations, to map how high-migrasome-score fibroblasts interact with their neighbors. The analysis predicted substantially stronger communication between these fibroblasts and both macrophages and dendritic cells than between fibroblasts and other populations. Among the inferred signaling routes, the macrophage migration inhibitory factor pathway, in which MIF engages the receptors CD74 and CXCR4, emerged as a leading candidate mechanism for fibroblast-to-dendritic-cell communication. This finding suggests that migrasome-active fibroblasts may actively sculpt the immune landscape of gastric tumors, potentially dampening or redirecting antitumor immune responses in ways that influence clinical outcomes.

The study’s most clinically ambitious component was the construction of a prognostic model that bridges the microscopic and macroscopic worlds. Using 101 machine learning algorithm combinations applied to bulk RNA sequencing data from 385 patients in The Cancer Genome Atlas training cohort, the researchers built what they call the Radiomics-Derived Migrasome-associated Gene Signature, or Rad_MGsig. The model integrates five migrasome-associated genes with nine radiomic features extracted from computed tomography scans of forty-six patients. Radiomic features capture quantitative patterns in medical images, such as texture and heterogeneity, that the human eye cannot reliably assess. By fusing imaging data with gene-expression programs, Rad_MGsig aims to translate what happens at the cellular level into information available from routine clinical imaging.

The performance figures reported for the signature are remarkable. In the training cohort, Rad_MGsig achieved area under the curve values of 0.96, 0.90, and 0.88 for predicting one-year, three-year, and five-year survival, respectively. In an independent validation cohort of 357 patients from the GSE84433 dataset, the values were 0.97, 0.90, and 0.90. Accuracy that remains this high across multiple time points and an external cohort is uncommon for prognostic models in oncology, and it suggests that migrasome biology captures a stable and consequential feature of gastric tumor behavior. If prospectively validated, the approach could help clinicians stratify patients for intensified treatment, closer surveillance, or, conversely, avoid unnecessary toxicity in those at lower risk.

To connect the computational findings to molecular mechanism, the researchers turned to laboratory experiments and structural modeling. Molecular docking simulations predicted that the experimental drug Uprosertib, an AKT inhibitor, binds TSPAN4 with the strongest predicted affinity among screened compounds, at negative 9.0 kilocalories per mole. Consistent with that prediction, Uprosertib inhibited the growth of gastric cancer cells in a dose-dependent manner, with half-maximal inhibitory concentrations of 0.368 micromolar in HGC-27 cells and 0.460 micromolar in AGS cells. Importantly, the drug attenuated the proliferative surge caused by forced TSPAN4 overexpression in AGS cells, indicating that the compound’s effect converges on the TSPAN4 axis. Knockdown and overexpression experiments supported the conclusion that TSPAN4 acts within tumor cells to activate the PI3K/AKT pathway and promote proliferation.

Spatial context provided the final piece of the puzzle. Using multiplex immunofluorescence on tumor tissue, the researchers visualized where TSPAN4-positive signals reside relative to fibroblast markers. They found TSPAN4-positive signals in close proximity to regions stained for Vimentin, a canonical fibroblast marker, specifically at the tumor-stroma interface, the dynamic border where malignant cells meet the supportive stromal tissue. This anatomical colocalization is consistent with a model in which fibroblast-derived migrasome activity and tumor-cell TSPAN4 signaling form a coupled program at the invasive front, where migration, communication, and proliferation converge. Such spatial coupling may explain why migrasome-associated gene signatures carry prognostic weight: they index an active, location-specific dialogue between tumor and stroma rather than an incidental byproduct of cell turnover.

The study, funded by the National Natural Science Foundation of China and the Natural Science Foundation of Hunan Province, was conducted under ethics approvals from Xiangya Hospital and Central South University, with written informed consent from all tissue donors and adherence to ARRIVE guidelines for the xenograft experiments. Its implications extend in several directions. For biomarker developers, Rad_MGsig offers a template for combining single-cell discovery with radiomics to create clinically deployable risk models. For drug developers, TSPAN4’s pro-proliferative role and the predicted binding of Uprosertib suggest a rational target, although the authors note that docking predictions and cell-line results will require substantial follow-up before clinical translation. For cancer biologists, the work adds migrasomes to the growing list of vesicle-mediated communication channels, alongside exosomes and other extracellular vesicles, that shape tumor progression. As migrasome research matures, the gastric cancer data suggest that these trailblazing organelles are more than cellular curiosities; they may be central actors in the tumor microenvironment’s conversation with cancer itself, and their fingerprints in genes and scans could ultimately guide therapy for one of medicine’s most stubborn diseases.

Subject of Research: Fibroblast-associated migrasome programs and TSPAN4 signaling in gastric cancer progression and prognosis

Article Title: Fibroblast-associated migrasome programs define TSPAN4-driven progression and clinical risk stratification in gastric cancer

Article References: Zhang, K., Ren, F., Ge, J., Huang, C., Kang, K., & Wu, Z. (2026). Fibroblast-associated migrasome programs define TSPAN4-driven progression and clinical risk stratification in gastric cancer. Cancer Cell International. https://doi.org/10.1186/s12935-026-04463-4

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04463-4

Keywords: gastric cancer, migrasomes, TSPAN4, fibroblasts, PI3K/AKT pathway, radiomics, single-cell RNA sequencing, spatial transcriptomics, prognostic signature, tumor microenvironment, Uprosertib, machine learning