{"id":31017,"date":"2025-04-30T00:49:54","date_gmt":"2025-04-29T22:49:54","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/04\/30\/mettl3-inhibition-restores-pd-l1-expression-and-cd8-t-cell-cytotoxic-function-in-immunotherapy-treated-gastric-cancer\/"},"modified":"2025-04-30T00:49:54","modified_gmt":"2025-04-29T22:49:54","slug":"mettl3-inhibition-restores-pd-l1-expression-and-cd8-t-cell-cytotoxic-function-in-immunotherapy-treated-gastric-cancer","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/04\/30\/mettl3-inhibition-restores-pd-l1-expression-and-cd8-t-cell-cytotoxic-function-in-immunotherapy-treated-gastric-cancer\/","title":{"rendered":"METTL3 inhibition restores PD-L1 expression and CD8+ T-cell cytotoxic function in immunotherapy treated gastric cancer"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Apr 29. doi: 10.1158\/2326-6066.CIR-24-1179. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>The efficacy of immunotherapy targeting PD-1\/PD-L1 in gastric cancer (GC) depends on PD-L1 expression level and infiltration of immune cells within the tumor microenvironment (TME). While methyltransferase-like 3 (METTL3) plays a role in the development and progression of GC, its mechanism of regulating the TME in GC remains unclear. In this study, we demonstrated that expression of PD-L1 is regulated by METTL3. We found that METTL3 mediated m6A modification of PDL1 mRNA in the 3&#8242;-untranslated region (UTR) and induced mRNA degradation through an m6A\/YTHDF2-dependent pathway in human GC cells. METTL3-knockdown or inhibition in GC cells significantly enhanced Jurkat cell migration and cytotoxic activity. In clinical GC tissue, a negative correlation was observed between the expression levels of PD-L1 and those of METTL3 or YTHDF2. In vivo, combination treatment with the METTL3 inhibitor STM2457 and PD-1 monoclonal antibody (mAb) resulted in a significant reduction in tumor growth, enhanced PD-L1 expression, and increased the infiltration of CD8+ T cells. Finally, lower METTL3 expression in tumors correlated with improved sensitivity to anti-PD-1 immunotherapy in patients. Our findings revealed that METTL3-mediated m6A modification of PDL1 mRNA levels represents an epigenetic mechanism regulating anti-tumor immunity in GC, and inhibiting METTL3 during PD-1 mAb treatment reshaped the TME, thereby establishing a promising treatment approach for enhancing immunotherapy efficacy in GC patients.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/40299705\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250429184950&amp;v=2.18.0.post9+e462414\">40299705<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-1179\">10.1158\/2326-6066.CIR-24-1179<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Apr 29. doi: 10.1158\/2326-6066.CIR-24-1179. Online ahead of print. ABSTRACT The efficacy of immunotherapy targeting PD-1\/PD-L1 in gastric cancer (GC) depends on PD-L1 expression level and infiltration of immune cells within the tumor microenvironment (TME). While methyltransferase-like 3 (METTL3) plays a role in the development and progression of GC, its mechanism of &#8230; <a title=\"METTL3 inhibition restores PD-L1 expression and CD8+ T-cell cytotoxic function in immunotherapy treated gastric cancer\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/04\/30\/mettl3-inhibition-restores-pd-l1-expression-and-cd8-t-cell-cytotoxic-function-in-immunotherapy-treated-gastric-cancer\/\" aria-label=\"Read more about METTL3 inhibition restores PD-L1 expression and CD8+ T-cell cytotoxic function in immunotherapy treated gastric cancer\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[55,42],"tags":[],"class_list":["post-31017","post","type-post","status-publish","format-standard","hentry","category-cancer-immunology-reserch","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/31017","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=31017"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/31017\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=31017"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=31017"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=31017"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}