Extracellular vesicles are not a recent discovery. They were first described in 1987, when researchers studying reticulocyte maturation observed vesicle formation during the differentiation of red blood cell precursors, a process then interpreted as a way for cells to discard unwanted membrane proteins. In the decades since, that view has been turned on its head. EVs are now understood to be sophisticated carriers of biological information, ferrying proteins, lipids, and nucleic acids, including non-coding RNAs, from one cell to another. Within tumors, this cargo transfer allows cancer cells to reprogram their neighbors, sculpt the tumor microenvironment, and prepare distant tissues for the arrival of metastatic cells. The review systematically organizes this evidence for gastric cancer, distinguishing the biological functions of naturally released vesicles from their translational potential as diagnostic tools and engineered therapeutics.

One of the most striking findings the authors compile concerns immune evasion. Gastric cancer-derived small extracellular vesicles can suppress antitumor immunity through multiple mechanisms. Exosomal PD-L1, the same checkpoint molecule targeted by blockbuster immunotherapy drugs, can be packaged into vesicles and circulated throughout the body, dampening CD8-positive T-cell activity and promoting the expansion of myeloid-derived suppressor cells. Studies cited in the review show that exosomal PD-L1 drives the progression of gastric cancer by expanding these immunosuppressive cell populations, and that chemotherapy itself can backfire in this regard: treatment with 5-fluorouracil was found to increase exosomal PD-L1 levels in patients with advanced disease, deepening immunosuppression even as it attacked the tumor directly.

The immune story extends well beyond PD-L1. Exosomes released by Epstein-Barr virus-associated gastric carcinoma cells have been shown to suppress the maturation of dendritic cells, the sentinels that normally initiate adaptive immune responses. Gastric cancer exosomes carrying miR-135b-5p impair the function of Vγ9Vδ2 T cells, an unconventional T-cell population with potent antitumor activity, by targeting the transcription factor specificity protein 1. Meanwhile, circular RNA circATP8A1 delivered by exosomes induces macrophage M2 polarization through the miR-1-3p/STAT6 axis, converting macrophages from inflammatory tumor killers into nurturing supporters of tumor growth. Exosomal biglycan adds another layer, promoting M2 polarization and activating CXCL10-mediated JAK/STAT1 signaling. Even traditional medicine formulations have been examined through this lens, with a modified Jianpi Yangzheng decoction shown to alter the content of the glycolytic enzyme PKM2 in gastric cancer cell-derived exosomes.

Metastasis, the process that most often seals a poor prognosis in gastric cancer, is another arena where EVs take center stage. The review highlights how gastric cancer-derived small extracellular vesicles facilitate peritoneal dissemination, one of the most feared patterns of spread in this disease, by inducing mesothelial-mesenchymal transition in the mesothelial cells that line the abdominal cavity. Exosomal miR-196a-5p remodels the pre-metastatic niche for peritoneal dissemination, while exosomal circPTBP3 drives peritoneal metastasis through the same mesothelial-mesenchymal transition pathway, and miR-106a promotes peritoneal spread by directly regulating Smad7. The liver is not spared either: in a widely cited Nature Communications study, exosome-delivered EGFR was shown to regulate the hepatic microenvironment in a way that promotes gastric cancer liver metastasis, effectively preparing distant soil before seed cells ever arrive.

Angiogenesis and stromal remodeling complete the picture of EV-mediated microenvironment manipulation. Gastric cancer-secreted exosomal X26nt increases angiogenesis and vascular permeability by targeting VE-cadherin, loosening the junctions between endothelial cells and potentially easing the intravasation of tumor cells into the bloodstream. Exosomal miR-128-3p promotes angiogenesis by targeting SASH1, and exosomal GRP78 enhances angiogenesis upon stimulation of vascular endothelial cells. Cancer-associated fibroblasts, key stromal allies of the tumor, can be recruited to the cause as well: exosomal miR-27a derived from gastric cancer cells regulates the transformation of ordinary fibroblasts into cancer-associated fibroblasts. In a bidirectional twist, tumor-associated macrophage-derived exosomes carrying functional apolipoprotein E promote the migration of gastric cancer cells, illustrating that vesicle traffic flows in both directions across the tumor-stroma interface.

Therapeutic resistance, whether to chemotherapy or to ferroptosis-inducing agents, also travels in vesicles. Paclitaxel-resistant gastric cancer cells promote epithelial-to-mesenchymal transition and chemoresistance in sensitive cells via exosomal delivery of miR-155-5p, effectively sharing their survival playbook with the rest of the tumor. Cisplatin-resistant cells accomplish something similar through an exosomal RPS3-mediated PI3K-Akt-cofilin-1 signaling axis. More recently, exosomes from tumor-associated neutrophils were shown to suppress ferroptosis, an iron-dependent form of regulated cell death, and confer chemoresistance via the miR-9-3p/ACSL4 axis. These findings suggest that intercepting vesicle-mediated communication could sensitize tumors to existing drugs, and the review notes that small molecule inhibitors targeting the release or uptake of gastric cancer-derived small extracellular vesicles may offer a strategy to disrupt oncogenic signaling at its source.

On the diagnostic front, the review frames EVs as a promising frontier for liquid biopsy. Because vesicles protect their molecular cargo from degradation by nucleases in the blood, circulating EVs offer a stable, minimally invasive window into tumor biology. Exosomal miRNAs have been used as circulating biomarkers to predict the development of hematogenous metastasis after surgery for stage II/III gastric cancer, while exosomal long noncoding RNA HOTTIP has been proposed as a novel diagnostic and prognostic biomarker, and exosome-protected MT1-MMP mRNA has been evaluated as a potential serum biomarker for the disease. In EBV-associated gastric cancer, vesicle-bound viral microRNAs such as miR-BART19-3p, which promotes proliferation by inhibiting GADD45B, could serve as fingerprints of the viral subtype. Serum-derived exosomal HER2 has been identified as a promising surrogate for assessing tissue HER2 status and predicting the efficacy of trastuzumab-based therapy, potentially sparing patients from invasive re-biopsies. Notably, a multi-cohort study published in Gut constructed an exosome non-coding RNA feature for non-invasive early detection of gastric cancer using machine learning, and a separate Nature Communications study demonstrated a single-test diagnosis of multiple cancer types using an Exosome-SERS-AI platform. The review envisions circulating EVs isolated by microfluidic chips being integrated with artificial intelligence-based algorithms to assist early diagnosis and prognostic prediction.

Perhaps the most forward-looking section of the review concerns engineered EVs as delivery vehicles. Exosomes are natural nanoparticles, biocompatible and capable of crossing biological barriers, and researchers have exploited these properties to load them with therapeutic cargo. Exosomes delivering hepatocyte growth factor siRNA suppressed tumor growth and angiogenesis in gastric cancer models, and exosome-delivered c-Met siRNA reversed chemoresistance to cisplatin. Engineered vesicles decorated with targeting ligands or antibodies have been explored for delivering siRNA or chemotherapeutic agents with greater precision, including targeted exosome delivery of the Hsp90 inhibitor 17-DMAG, which enhanced gastric cancer treatment efficacy. Responsive dual-targeting exosomes have been designed as drug carriers for combination cancer immunotherapy, and elaborate nanovehicles combining exosomes with gold-protein shells and photosensitizers have enabled real-time fluorescence imaging alongside enhanced targeted photodynamic therapy. The engineering toolkit also extends to surface functionalization and loading strategies, from membrane squeezing approaches informed by coarse-grained molecular simulation to PEGylation with copper-64 labeling for positron emission tomography tracking of vesicle biodistribution and tumor retention.

The authors are candid about the obstacles standing between this science and the clinic. Technical limitations in isolation and characterization remain significant, as different separation methods alter the physicochemical properties of vesicles and their clearance from blood circulation, and the field’s MISEV2023 guidelines underscore how much standardization is still needed. Tumor-derived vesicles can even act as a barrier to therapeutic nanoparticle delivery, competing with engineered carriers and complicating biodistribution. Lack of standardization and insufficient clinical validation are cited as the central challenges facing EV-based precision medicine, alongside the pharmacokinetic complexities of mononuclear phagocyte system uptake. Yet the trajectory is clear: from Zitvogel’s landmark 1998 demonstration that dendritic cell-derived exosomes could eradicate established murine tumors, through natural killer cell-derived exosomal miR-186 inhibiting neuroblastoma growth, to today’s AI-assisted exosome diagnostics, extracellular vesicles have moved from cellular curiosities to central actors in gastric cancer research. If the technical and regulatory hurdles can be cleared, these nanoscale messengers may ultimately deliver on both halves of their promise, catching the disease earlier and carrying treatments more precisely to where they are needed.

Subject of Research: The roles of extracellular vesicles in gastric cancer progression, diagnosis, and engineered therapeutic delivery

Article Title: Extracellular vesicles in gastric cancer: biological functions, clinical applications, and engineering strategies

Article References: Shi, X., Shao, C., & Wang, J. (2026). Extracellular vesicles in gastric cancer: biological functions, clinical applications, and engineering strategies. Medical Oncology, 43(10), Article 272. https://doi.org/10.1007/s12032-026-03382-8

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03382-8

Keywords: gastric cancer, extracellular vesicles, exosomes, liquid biopsy, tumor microenvironment, PD-L1, peritoneal metastasis, drug delivery, biomarkers, immunotherapy, nanotechnology, artificial intelligence