{"id":62761,"date":"2026-04-28T01:12:26","date_gmt":"2026-04-27T23:12:26","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/04\/28\/lenvatinib-combined-with-pd-1-blockade-therapy-benefits-gastric-cancers-through-immunosuppressive-macrophage-modulation\/"},"modified":"2026-04-28T01:12:26","modified_gmt":"2026-04-27T23:12:26","slug":"lenvatinib-combined-with-pd-1-blockade-therapy-benefits-gastric-cancers-through-immunosuppressive-macrophage-modulation","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/04\/28\/lenvatinib-combined-with-pd-1-blockade-therapy-benefits-gastric-cancers-through-immunosuppressive-macrophage-modulation\/","title":{"rendered":"Lenvatinib combined with PD-1 blockade therapy benefits gastric cancers through immunosuppressive macrophage modulation"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2026 Apr 27. doi: 10.1158\/2326-6066.CIR-25-0982. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>The combination of multikinase inhibitors with PD-1 blockade therapy has emerged as a promising strategy to overcome resistance to PD-1 blockade monotherapy across multiple cancer types, including gastric cancer (GC). Here, we report that the multikinase inhibitor lenvatinib selectively reduced the number of CD206+CD163+ immunosuppressive macrophages in the tumor microenvironment (TME) and increased antitumor immunity. Longitudinal immunoprofiling was conducted with paired (pre- and posttreatment) tumor samples from patients with advanced GC who received first- or second-line combination therapy with lenvatinib and pembrolizumab in the EPOC1706 clinical trial. Patients with abundant CD206+CD163+ immunosuppressive macrophage infiltration exhibited favorable responses to combination therapy, accompanied by a significant posttreatment reduction in these cells. While this immunosuppressive macrophage infiltration was associated with resistance to PD-1 blockade monotherapy, it predicted a response to combination treatment: eight of the 9 patients with &gt;440 CD206+CD163+ immunosuppressive macrophages\/mm\u00b2 responded, whereas none of the 8 patients who received monotherapy responded. Mechanistically, lenvatinib inhibited PDGFR\u03b1 (platelet-derived growth factor receptor \u03b1)\/FGFR (fibroblast growth factor receptor)-dependent p38 MAPK (mitogen-activated protein kinase) and AKT signaling pathways in F4\/80highCD11bint immunosuppressive macrophages, triggering endoplasmic reticulum stress and an unresolved unfolded protein response, resulting 4 in their apoptosis. Furthermore, in multiple animal models, the therapeutic efficacy of the combination was observed in tumors with abundant immunosuppressive macrophages with activated PDGFR\/FGFR-AKT\/p38 MAPK signaling. Therefore, we propose that the abundance of immunosuppressive macrophages in the TME could serve as a predictive biomarker for patient stratification to guide rational anti-PD-1-based combination therapy in GC, enabling mechanism-based combination cancer immunotherapy.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/42044259\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20260427191226&amp;v=2.19.0.post6+133c1fe\">42044259<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-25-0982\">10.1158\/2326-6066.CIR-25-0982<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2026 Apr 27. doi: 10.1158\/2326-6066.CIR-25-0982. Online ahead of print. ABSTRACT The combination of multikinase inhibitors with PD-1 blockade therapy has emerged as a promising strategy to overcome resistance to PD-1 blockade monotherapy across multiple cancer types, including gastric cancer (GC). Here, we report that the multikinase inhibitor lenvatinib selectively reduced the number &#8230; <a title=\"Lenvatinib combined with PD-1 blockade therapy benefits gastric cancers through immunosuppressive macrophage modulation\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2026\/04\/28\/lenvatinib-combined-with-pd-1-blockade-therapy-benefits-gastric-cancers-through-immunosuppressive-macrophage-modulation\/\" aria-label=\"Read more about Lenvatinib combined with PD-1 blockade therapy benefits gastric cancers through immunosuppressive macrophage modulation\">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-62761","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\/62761","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=62761"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/62761\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=62761"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=62761"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=62761"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}