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This study demonstrates through analysis of 99 NPC clinical samples (primary tumors) that Epstein-Barr virus-encoded small RNAs (EBERs) positivity in ECs significantly correlates with N stage (lymphatic metastasis,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05), M stage (distant metastasis,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.01), and advanced clinical stage (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.01), while immunological profiling reveals concomitant reductions in B-cell proportions (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.01) in patients with EBERs-positive ECs. Through comprehensive\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      modeling employing EBV particle infection, Transwell coculture, and direct-contact systems with EBV-positive Akata and Raji cells, we observed that human lymphatic endothelial cells actively internalize infected lymphocytes, with RT-PCR confirming expression of EBV oncogenes (EBNA1, LMP1, and LMP2)\u2014particularly in direct-contact conditions\u2014alongside significant upregulation of endocytosis-related genes Rab5a and EHD1 and ultrastructural evidence of phagosome formation. These findings collectively suggest that phagocytic uptake of EBV-infected lymphocytes or their components may serve as a primary infection mechanism for ECs, potentially establishing an immunosuppressive microenvironment that contributes to tumor progression and poor clinical outcomes, though the exact molecular pathways require further elucidation.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Clinical investigations of NPC specimens identified EBERs-positive endothelial cells as clinically significant biomarkers, demonstrating robust correlations with lymphatic metastasis (\n                        <jats:italic toggle=\"yes\">P<\/jats:italic>\n                        &lt; 0.05), distant metastasis (\n                        <jats:italic toggle=\"yes\">P<\/jats:italic>\n                        &lt; 0.01), and advanced tumor staging (\n                        <jats:italic toggle=\"yes\">P<\/jats:italic>\n                        &lt; 0.01), while immunological profiling of affected patients revealed concomitant reductions in B-cell populations (\n                        <jats:italic toggle=\"yes\">P<\/jats:italic>\n                        &lt; 0.01), collectively indicative of systemic immunoregulatory status. Furthermore, integrative experimental approaches incorporating live-cell dynamic imaging, single-cell transcriptional profiling, and ultrastructural electron microscopy provided compelling evidence that endothelial phagocytosis of lymphocytes serves as a principal route for EBV cellular entry and subsequent modulation of the NPC tumor microenvironment.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.03427-24","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T12:00:26Z","timestamp":1752062426000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Epstein-Barr virus (EBV) infection of endothelial cells via endocytosis is associated with a poor prognosis in nasopharyngeal 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