{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:31:16Z","timestamp":1787668276481,"version":"build-2736575974"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Natural killer cells (NK cells) play a critical role in the surveillance of tumor immunity. However, NK cell-based immunotherapy, including autologous and allogeneic NK cell reinfusion, has not brought significant clinical benefits to patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To identify factors that control the intrinsic cytotoxicity of NK cells, we utilized the histone deacetylase inhibitor valproic acid (VPA) to develop a NK cell cytotoxicity suppression model. With RNA-seq and functional assays, we identified a lncRNA,\n                      <jats:italic>LINC02470<\/jats:italic>\n                      , as a negative regulatory factor of NK cell-mediated cytotoxicity.\n                      <jats:italic>LINC02470<\/jats:italic>\n                      was significantly upregulated in VPA-treated NK cells and was negatively associated with the cytotoxicity of NK cells. Knockdown of\n                      <jats:italic>LINC02470<\/jats:italic>\n                      enhanced, and overexpression of\n                      <jats:italic>LINC02470<\/jats:italic>\n                      suppressed antitumor activity in NK-92MI cells and human primary NK cells. Then reverse transcription-associated capture sequencing (RAT-seq) and mechanistic studies were explored to find the target and mechanisms of\n                      <jats:italic>LINC02470<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      By RAT-seq we found that\n                      <jats:italic>LINC02470<\/jats:italic>\n                      functioned by targeting the Natural cytotoxicity triggering receptor 1 (\n                      <jats:italic>NCR1<\/jats:italic>\n                      ) gene, which encodes the activating receptor NKp46 involved in the natural cytotoxicity. Mechanistic studies revealed that\n                      <jats:italic>LINC02470<\/jats:italic>\n                      interacted with the regulatory elements of\n                      <jats:italic>NCR1<\/jats:italic>\n                      and blocked the formation of an intrachromosomal interaction that is required for optimal expression of\n                      <jats:italic>NCR1<\/jats:italic>\n                      . In addition,\n                      <jats:italic>LINC02470<\/jats:italic>\n                      inhibited the synthesis of\n                      <jats:italic>NCR1<\/jats:italic>\n                      enhancer RNA. Through these dual mechanisms,\n                      <jats:italic>LINC02470<\/jats:italic>\n                      induced a suppressive epigenotype in the\n                      <jats:italic>NCR1<\/jats:italic>\n                      promoter and suppressed the expression of the\n                      <jats:italic>NCR1<\/jats:italic>\n                      gene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>LINC02470-NCR1<\/jats:italic>\n                      axis identified in this study may serve as a novel target to improve therapeutic intervention of NK cells in tumor immunotherapy.\n                    <\/jats:p>\n                  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