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BC\u2010derived exosomes influence intercellular communication within the tumor microenvironment, driving metastatic progression. However, the precise mechanisms by which exosomes facilitate LN metastasis in BC remain unclear. We performed small RNA sequencing on serum exosomes to identify Piwi\u2010interacting RNAs (piRNAs) associated with BC LN metastasis. Functional investigations of exosomal piR\u2010hsa\u201028212 included in\u00a0vitro assays for migration and tube formation of human lymphatic endothelial cells (HLECs), alongside an in\u00a0vivo footpad\u2010popliteal LN metastasis model. Specific interactions between piR\u2010hsa\u201028212 and TBX1 (T\u2010box transcription factor 1), as well as TBX1 and VEGF receptor 3 (VEGFR3), were validated through luciferase reporter assays. The stability of TBX1 mRNA was analyzed by actinomycin D assay. RNA pulldown, RNA immunoprecipitation (RIP), and RNA fluorescence in\u00a0situ hybridization (FISH) assays were conducted to explore the interaction between piR\u2010hsa\u201028212 and METTL3. PiR\u2010hsa\u201028212 was significantly upregulated in serum exosomes of BC patients with LN metastasis. Exosomal piR\u2010hsa\u201028212 enhanced HLECs migration and tube formation in\u00a0vitro and promoted lymphangiogenesis and LN metastasis in\u00a0vivo. Mechanistically, exosomal piR\u2010hsa\u201028212 transferred from BC cells to HLECs stabilized TBX1 mRNA, thereby upregulating VEGFR3 expression. In BC cells, piR\u2010hsa\u201028212 directly bound to and stabilized METTL3 protein, modulating N6\u2010methyladenosine (m6A) methylation of vascular endothelial growth factor C (VEGFC) mRNA and consequently increasing VEGFC expression and secretion. Collectively, these findings reveal an exosome\u2010mediated piRNA regulatory mechanism that synergistically amplifies VEGFC\/VEGFR3 signaling to drive LN metastasis in BC, highlighting piR\u2010hsa\u201028212 as a potential therapeutic target.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    KYLL\u20102022\u2010338\n                  <\/jats:p>","DOI":"10.1111\/cas.70450","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T10:38:42Z","timestamp":1781606322000},"page":"2733-2751","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\u2010Derived Exosomal\n                    <scp>piR<\/scp>\n                    \u2010hsa\u201028212 Promotes Lymphatic Metastasis in Breast Cancer"],"prefix":"10.1111","volume":"117","author":[{"given":"Yafen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gynecology The Second Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gynecology The Second Qilu Hospital of Shandong University  Jinan Shandong China"},{"name":"Advanced Medical Research Institute of Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory The Second Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory The Second Qilu Hospital of Shandong 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