---
title: "Extracellular Y RNA Fragments and a Proposed Role for YBX1 in Macrophage Responses in Gastrointest"
id: "frontiers-in-immunology-17-extracellular-y-rna-fragments-in-gastrointestinal-cancer-and-a-proposed-role"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-extracellular-y-rna-fragments-in-gastrointestinal-cancer-and-a-proposed-role"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902611"
published_at: "2026-10-20T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Extracellular Y RNA Fragments and a Proposed Role for YBX1 in Macrophage Responses in Gastrointest
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-extracellular-y-rna-fragments-in-gastrointestinal-cancer-and-a-proposed-role
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902611)
- **Published At:** 2026-10-20T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source is a review article titled “Extracellular Y RNA fragments in gastrointestinal cancer and a proposed role for YBX1 in macrophage responses.” - The paper focuses on **Y RNA** fragments found outside cells in the context of **gastrointestinal cancer**, and on a hypothesized involvement of **YBX1** in macrophage signaling or function. - The JINA source page provided only the article metadata and site navigation; the body text of the review, experimental details, and specific clinical or mechanistic findings were not present in the provided source content. - Because the source did not include study methods or results, this rewrite does not invent experimental details, numeric results, or patient cohort descriptions; investigators’ specific data were not available on the provided page. - The review format implies synthesis of existing literature rather than new primary data, but the source did not list the studies cited, so exact references and their outcomes could not be summarized here. - The authors apparently propose a mechanistic link between extracellular **Y RNA** fragments and macrophage behavior mediated by **YBX1**, though the source did not report supporting assays, signaling pathways, or functional readouts. - Open questions left by the available source: which Y RNA fragments (sequence/length) are implicated, how extracellular Y RNA are delivered to macrophages, whether **YBX1** binding was demonstrated in macrophages, and what clinical correlations exist with tumor stage or patient outcomes. - The provided content did not report translational implications, therapeutic strategies, or regulatory milestones; those items are therefore omitted to preserve source fidelity. - Readers should consult the full Frontiers in Immunology review for complete mechanistic detail, referenced primary studies, experimental evidence, and author-stated limitations because those elements were not included on the captured page.
## Clinical Analysis & Structured Key Points
Frontiers | Extracellular Y RNA fragments in gastrointestinal cancer and a proposed role for YBX1 in macrophage responses REVIEW article Front. Immunol. , 20 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1902611 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Editor & Reviewers Edited by H F Hai Fang Reviewed by J C Jiali Cheng M A Marco Antonio Barajas Mendiola Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 GI cancer models and macrophage readouts for testing the proposed pathway. View in article Table 2 Experimental requirements for testing EV-associated Y RNA effects on macrophages. View in article REVIEW article Front. Immunol. , 20 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1902611 Extracellular Y RNA fragments in gastrointestinal cancer and a proposed role for YBX1 in macrophage responses X W Xitan Wang † F W Fuli Wang † W T Wei Tian * Department of Oncology, Zibo Central Hospital, Zibo, Shandong, China Article metrics View details Abstract Tumor-derived extracellular vesicles (EVs) can alter macrophage responses, but the contribution of individual RNA cargoes remains difficult to establish. Y RNA-derived fragments are candidate mediators whose mechanisms after EV exposure have not been conclusively defined across physiological settings. This review examines reported EV-associated macrophage effects in gastrointestinal (GI) cancer, Y RNA studies from other diseases, and a possible role for RNA modifications and RNA-binding proteins. Separate experimental systems link YBX1 protein methylation to fragment sorting, damage-associated Y3 RNA methylation to YBX1 binding and PARP1 activity, and extracellular hY4 to monocyte responses through TLR7. These observations do not establish a continuous pathway in GI cancer. We propose that a sequence-defined Y RNA fragment could reach recipient macrophages, bind YBX1 in an m5C-sensitive manner, and alter a measurable molecular process before changing macrophage function. Whether this occurs, whether RNA methylation precedes or follows transfer, and whether the response supports tumor growth remain unresolved. A cardiac study using a synthetic Y RNA fragment reported reduced inflammatory-cell recruitment, illustrating that RNA responses can differ with disease and treatment context. The review distinguishes vesicle uptake from functional RNA delivery and considers endosomal sensing, other EV cargoes, and donor-cell effects as alternative explanations. Testing this hypothesis will require demonstrating functional delivery of a defined Y RNA fragment and YBX1-dependent macrophage effects in the same GI cancer model. 1 Introduction Tumor-derived extracellular vesicles (EVs) are a possible source of signals that alter neighboring cells ( 1 ). Tumor-associated macrophages influence immune suppression and tumor progression ( 2 ), motivating investigation of the signals that change their function in gastrointestinal (GI) cancer. EV preparations contain proteins, lipids, and RNAs, and their effects on macrophages cannot be assigned to a particular RNA solely because that RNA is detected in the preparation or in exposed cells. This review asks which observations support RNA-dependent macrophage responses and what additional evidence would be required to implicate Y RNA-derived fragments. MicroRNAs have been widely studied as candidate EV-associated signals in cancer ( 3 ), although efficient functional transfer cannot be assumed in every donor-recipient system ( 4 ). Other small non-coding RNAs include fragments of transfer RNAs, ribosomal RNAs, and Y RNAs that can arise independently of canonical microRNA biogenesis ( 5 ). Y RNA-derived fragments have been detected in extracellular RNA profiles ( 6 , 7 ). Their Pol III origin and broader biological context are reviewed separately ( 8 ). Studies of Y RNA processing and extracellular release establish roles for RNA structure and associated proteins ( 9 , 10 ). A separate DNA-damage study investigated Y3-fragment methylation and YBX1 binding ( 11 ). These observations do not establish a general modification-dependent mechanism for all extracellular Y RNA fragments. The GI cancer literature reports macrophage responses to tumor EV preparations containing several candidate small RNAs, whereas Y RNA-specific myeloid evidence comes mainly from leukemia and non-tumor models. We examine these disease-specific observations before introducing a possible YBX1-dependent mechanism. Circulating Y RNA measurements are discussed separately because they do not establish a tumor source, delivery to macrophages, or a functional effect. YBX1 warrants consideration because separate studies associate it with Y3-fragment activity after transfer, EV-associated RNA-binding proteins, and methylation-dependent sorting of an hY4 fragment ( 11 – 13 ). The proposed extension to GI macrophages requires direct testing at each step. The review therefore compares this hypothesis with endosomal RNA sensing and with effects of other EV components or soluble factors, rather than assuming that YBX1 explains all reported macrophage responses. We distinguish three questions throughout: whether a Y RNA species is present in tumor-associated samples, whether it reaches a recipient compartment where it can act, and whether it causes a macrophage response through a defined mechanism. Evidence for one question does not answer the others. The tRNA-derived fragment tRF-3022b is included as a different small-RNA class with a cytokine-associated mechanism studied in a tumor-cell/macrophage system; it is not a Y RNA fragment. 2 Y RNA biogenesis modifications and RNA binding proteins 2.1 Y RNAs and the Ro60 ribonucleoprotein Human Y RNAs are small, structured RNA polymerase III transcripts of approximately 80–110 nt that bind RO60, also known as SS-A/TROVE2 ( 14 ). Ro60 is a ring-shaped RNA-binding protein that recognizes structured or misfolded RNAs. Biochemical and bacterial studies support roles in RNA quality control and turnover, but the exact functions vary across organisms. Ro60-Y RNA complexes are also clinically relevant autoantigens in Sjogren syndrome and systemic lupus erythematosus ( 14 ). 2.2 Y RNA fragmentation differs from canonical microRNA biogenesis Under cellular stress and apoptosis, Y RNAs can be processed into 5-prime and 3-prime fragments, with fragment sizes and dependencies varying by RNA species and cell system ( 9 ). The processing study identified structural requirements for RNY5 cleavage and a role for RO60, with RNase L contributing in some cells ( 9 ). A separate knockout analysis in HCT116 cells found that most tRNA-, Y RNA-, and rRNA-derived small-RNA signals were not reduced by loss of DROSHA, DGCR8, XPO5, or DICER ( 5 ). This supports a distinction from canonical microRNA biogenesis in that system, but does not establish that every Y RNA fragment in every tissue is independent of these factors. Because RO60 perturbation can change fragment production, EV-associated abundance must be interpreted alongside intracellular fragment abundance before a sorting effect is inferred. 2.3 Evidence for Y RNA methylation and YBX1 binding Evidence for m5C-sensitive YBX1 binding comes from distinct experimental contexts. In the ionizing-radiation study by Shaw et al., synthetic Y3 5-prime ysRNA oligonucleotides showed damage-associated nuclear localization and NSUN2-dependent m5C modification in complementary mechanistic assays ( 11 ). The study connects Y RNA/YBX1 activity to PARP1-associated repair, but does not directly map the methylation history of a naturally transferred EV fragment. Separately, mRNA studies connect NSUN2/YBX1 activity with transcript stability ( 15 , 16 ). The bladder-cancer study identifies W65 in the YBX1 cold-shock domain as important for m5C recognition ( 15 ). These mRNA findings do not define the activity of a short non-coding Y RNA fragment. The relevant methylation site, timing, reader requirement, and downstream response in GI macrophages remain unknown. 2.4 Regulation of EV loading EV RNA profiles can differ from those of donor cells. Proteo-transcriptomic analysis identified co-enrichment of RNY3 and YBX1, while its IGF2BP2-related analysis concerned vault RNA; this does not establish IGF2BP2 as a Y RNA-binding or sorting factor ( 12 ). A separate lung cancer study demonstrated YBX1-methylation-dependent export of an hY4-derived fragment ( 13 ). In activated THP1-derived macrophages, Y RNA subtypes and RO60 showed altered intracellular distribution and extracellular release ( 10 ). Those measurements do not establish sequence-resolved fragment loading or RO60-dependent sorting. The responsible RNA species and regulatory mechanisms therefore require testing in each donor-cell system. 3 Evidence for EV associated macrophage responses 3.1 GI tumor EV studies and the limits of RNA transfer evidence Studies in GI cancer report macrophage responses associated with EV preparations and candidate RNA cargoes. In CRC, miR-934 was linked to PTEN/PI3K-AKT signaling, macrophage M2-polarization readouts, and CXCL13-associated liver metastasis ( 17 ). In pancreatic cancer, hypoxic tumor EVs enriched in miR-301a-3p were linked to macrophage polarization through PTEN/PI3K-gamma ( 18 ). HCC studies reported effects of EV-associated miR-23a-3p on macrophage PD-L1 and CD8-positive T-cell activity ( 19 ), and of miR-21-5p on RhoB-associated polarization ( 20 ). These studies support investigation of EV-associated macrophage responses, but each requires assessment of RNA dose, carrier purity, delivery, and RNA-specific causality. None establishes a Y RNA-fragment/YBX1/m5C mechanism in GI cancer. The mutant-p53 CRC study is retained with a specific qualification ( 21 ). The sequence commonly called miR-1246 overlaps a fragment of RNU2-1, the U2 small nuclear RNA, and can be detected by assays described as miR-1246 assays ( 22 ). Macrophages also contain endogenous U2 RNA. Increased signal in exposed macrophages, tissue co-localization, or responses to a synthetic mimic therefore cannot alone distinguish donor-derived transfer from endogenous RNA or establish canonical microRNA activity. Full fragment boundaries, orthogonal size-resolved assays, donor-specific tracing, and sequence-specific loss-and-rescue experiments are needed to assign transfer and function. EV uptake and functional RNA delivery are separate measurements. Albanese et al. found that EV interaction with recipient cells did not generally produce efficient functional miRNA transfer in their experimental systems ( 4 ). This does not exclude all EV-RNA activity, but it prevents efficient transfer from being treated as a default assumption. For Y RNA studies, absolute cargo copies, exposure dose, and recipient-compartment access must be quantified. EV-enriched and EV-depleted fractions, appropriate soluble-factor controls, and RNase treatment with and without membrane disruption can help assess carrier association. Donor-specific labeling must control for free label, precursor carryover, and labeling-induced changes in RNA behavior. 3.2 A tRNA fragment associated with cytokine signaling in CRC In CRC, tRF-3022b is a tRNA-derived fragment detected in tumor tissue and plasma exosomes ( 23 ). Its knockdown increased M2-polarization readouts in the experimental tumor-cell/macrophage system. The study investigated interactions involving LGALS1 and MIF, including RNA-protein binding assays using CRC-cell and THP1-cell material. These findings should not be reduced to an exclusively donor-cell mechanism. They also do not establish that native EVs deliver the fragment to macrophages or that recipient YBX1 recognizes it. The example therefore concerns a different small-RNA class and cytokine-associated regulation, with a direction and mechanism that must remain distinct from the proposed GI Y RNA pathway. 3.3 Y RNA studies in myeloid cells outside GI cancer For Y RNA species, the closest myeloid evidence discussed here comes from systems outside the gastrointestinal tract. In chronic lymphocytic leukemia (CLL), Haderk et al. linked tumor EV-associated hY4 to cytokine release and PD-L1 expression through TLR7 ( 24 ). A later study reported preferential uptake of B-cell-receptor-stimulated CLL EVs by monocytes and hY4-associated CCL24 expression and nurse-like differentiation ( 25 ). These studies provide a reason to investigate Y RNA responses in myeloid cells, but neither establishes m5C-sensitive recognition by recipient-cell YBX1. Reported hY4 species must also be distinguished from sequence-defined shorter fragments before comparing mechanisms across studies. YF1 is a 56-nt Y RNA-derived fragment originally identified in cardiosphere-derived EVs. In a transgenic mouse model of hypertrophic cardiomyopathy, intravenous administration of synthetic YF1 reduced inflammatory-monocyte mobilization and macrophage accumulation and altered macrophage transcriptional responses ( 26 ). Because the intervention used the synthetic RNA on its own, this study does not establish physiological delivery by native EVs. A separate nematode study reported transfer of EV-associated small RNAs to mammalian cells and suppression of type-2 innate responses ( 27 ); it did not isolate a Y RNA-specific contribution to the immune phenotype. These non-GI observations provide a rationale for testing Y RNA-dependent macrophage responses in GI tumors, but they do not predict the receptor or the direction of the response. hY4-related RNAs appear in both the lung cancer sorting study and leukemia myeloid studies ( 13 , 24 , 25 ), yet their fragment boundaries, modification states, and biological contexts cannot be treated as interchangeable. An immunosuppressive response is one candidate outcome suggested by the GI EV literature, not an established or inevitable property of Y RNA cargo. The TLR7 mechanism provides a demonstrated sensing alternative, while the synthetic-YF1 study illustrates a different RNA intervention and disease context. Figure 1 and 2 summarize these distinctions. In Figure 1 and 2 , P1 denotes the untested GI tumor-to-myeloid Y RNA/YBX1 hypothesis specified in Section 6. The separate lung-cancer, cultured-cell DNA-repair, leukemia, and cardiac examples provide context; they do not demonstrate a single continuous pathway in GI cancer. Figure 1 Proposed Y RNA-fragment export and myeloid response in GI cancer. P1 denotes the untested GI hypothesis defined in Section 6. The enclosing GI donor-cell box identifies the proposed setting; it does not locate all supporting experiments in GI cancer. Solid arrows summarize relationships supported in their original experimental contexts, whereas dashed arrows indicate proposed or unresolved connections. Box borders indicate visual grouping, not evidence strength. RO60 denotes an upstream influence on fragment accumulation, not an established sorting factor ( 9 ). K264me denotes YBX1 protein methylation, supported for hY4-fragment export in a lung-cancer model, and is distinct from RNA m5C ( 13 ). IGF2BP2 is shown only as an EV-associated candidate; the cited study does not demonstrate Y RNA binding or sorting by this protein ( 12 ). Its placement and the plus sign do not establish co-binding or a YBX1-containing complex. The green uptake route requires demonstration of donor-derived RNA access to the relevant intracellular compartment; uptake alone does not establish functional delivery. Recipient YBX1 binding, m5C dependence, the effector step, and the TAM-like outcome remain predictions. The orange branch depicts the separate lung-cancer donor-depletion example ( 13 ). The gray epithelial comparator refers to cultured-cell ionizing-radiation experiments and complementary synthetic-Y3 assays involving NSUN2, YBX1, and PARP1 ( 11 ); it does not show GI macrophage reprogramming or trace the methylation history of native EV cargo. RNA m5C timing before or after export remains unresolved. EV, extracellular vesicle; GI, gastrointestinal; TAM, tumor-associated macrophage. Figure 2 Proposed myeloid outcomes and separate experimental comparators. P1 is the untested GI Y RNA/YBX1 hypothesis defined in Section 6. Dashed connections require validation; solid relationships refer only to the original experimental context. Box borders indicate visual grouping, not evidence strength. The green TAM-like program is a candidate outcome, not an established effect of GI Y RNA cargo. CCL24, SPP1, IL10, TGFB1, and CD274 are phenotypic readouts, not established direct YBX1 targets; immune suppression requires functional testing. The revised label “GI tumor EV-associated macrophage effects: reported for other RNAs” refers to macrophage effects reported in selected GI EV/RNA studies ( 17 – 21 ). It does not establish efficient physiological RNA delivery, equivalent evidence across RNA classes, or a Y RNA mechanism. The tRF-3022b example discussed in Section 3.2 concerns a tRNA fragment and is not a Y RNA component of P1 ( 23 ). The blue CLL comparator represents hY4-associated TLR7-dependent cytokine and PD-L1 responses; neither recipient YBX1 nor m5C dependence was established ( 24 ). The gray DNA-repair comparator concerns a distinct irradiation setting ( 11 ). The separate tissue-protective comparator refers to synthetic 56-nt YF1 administration in cardiac disease, not native EV delivery or a demonstrated GI antitumor effect ( 26 ). The plasma/EV box indicates an association requiring carrier resolution, source attribution, and validation ( 38 , 39 ); its dashed connection does not establish GI tumor origin. IGF2BP2 is shown only as an EV-associated candidate; the cited study does not demonstrate Y RNA binding or sorting by this protein ( 12 ). Uptake does not demonstrate functional delivery. CLL, chronic lymphocytic leukemia; CRC, colorectal cancer. 3.4 Macrophage heterogeneity and tumor immune context Single-cell analysis of human CRC and corresponding mouse models identified macrophage subsets with different inflammatory and pro-angiogenic or tumor-associated transcriptional programs ( 28 ). A pan-cancer myeloid atlas likewise identified heterogeneous TAM populations with variable marker programs across cancer types ( 29 ). We therefore propose describing recipient responses using context-specific transcriptional and functional measurements rather than a binary M1/M2 classification. CCL24, SPP1, and PD-L1 are candidate readouts in the proposed experiments; no study reviewed here establishes that an EV-delivered Y RNA fragment produces a particular GI TAM subset through YBX1. Any macrophage response should be interpreted alongside the baseline tumor immune environment ( 30 ). A change in CD163, CD206, or SPP1 expression alone does not demonstrate suppression of antitumor immunity. Studies should also measure macrophage effects on T-cell activation, proliferation, or cytotoxicity and account for pre-existing inflammatory and differentiation states. These functional data are needed before assigning therapeutic significance to an EV-associated change in macrophage markers. 3.5 DNA damage studies and their relevance to GI cancer The key EV-transfer experiments in Shaw et al. used ionizing radiation, not ultraviolet irradiation ( 11 ). EVs from irradiated donors were applied to recipient cells, including recipients subsequently irradiated to assess radioprotection. Complementary assays linked Y3 5-prime ysRNA, NSUN2, YBX1, and PARP1 residency at DNA breaks. The reported endpoint concerns damage repair; it does not establish a change in macrophage differentiation or immune function. Moreover, several mechanistic assays used synthetic oligonucleotides, so they should not be described as direct tracking of methylation on naturally delivered EV cargo. Acute irradiation in this model
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