{"id":38541,"date":"2025-07-19T00:47:47","date_gmt":"2025-07-18T22:47:47","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/07\/19\/spp1-tumor-associated-macrophages-drive-immunotherapy-resistance-via-cd8-t-cell-dysfunction-in-clear-cell-renal-cell-carcinoma\/"},"modified":"2025-07-19T00:47:47","modified_gmt":"2025-07-18T22:47:47","slug":"spp1-tumor-associated-macrophages-drive-immunotherapy-resistance-via-cd8-t-cell-dysfunction-in-clear-cell-renal-cell-carcinoma","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/07\/19\/spp1-tumor-associated-macrophages-drive-immunotherapy-resistance-via-cd8-t-cell-dysfunction-in-clear-cell-renal-cell-carcinoma\/","title":{"rendered":"SPP1+ Tumor-associated Macrophages Drive Immunotherapy Resistance via CD8+ T-Cell Dysfunction in Clear Cell Renal Cell Carcinoma"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Jul 18. doi: 10.1158\/2326-6066.CIR-24-1146. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Tumor-associated macrophages (TAMs) are key regulators of tumor immunity. With advances in single-cell analyses, SPP1+ TAMs have been observed across multiple tumor sites. However, their clinical relevance and phenotypic characteristics in clear cell renal cell carcinoma (ccRCC) have not been comprehensively delineated. Using patient-level data from two in-house cohorts (n=355) we explored the relationship between SPP1+ TAM infiltration and therapeutic response as well as prognosis in ccRCC. Four publicly available datasets consisting of 1,741 ccRCC patients were included for external validation. Cytometry by time-of-flight (CyTOF) and flow cytometry were utilized to phenotype SPP1+ TAMs and establish their impact on CD8+ T cells. Further, we established an ex vivo culture system to test the potential therapeutic value of targeting SPP1 alone and in conjunction with PD-1 inhibitors in ccRCC. We found that patients with high SPP1+ TAM infiltration exhibited worse response to immunotherapy and dismal prognosis in ccRCC. SPP1+ TAMs exhibited an immunosuppressive and pro-tumor phenotype, and were related to impaired effector function and terminal differentiation of CD8+ T cells. Blockade of SPP1 mitigated the pro-tumor tumor microenvironment and reinvigorated CD8+ T-cell function. Combining PD-1 blockade with SPP1 blockade boosted the expansion of CD8+ T cells and enhanced antitumor efficacy. Together, these data indicate that elevated infiltration of SPP1+ TAMs is related to worse response to immunotherapy and dysfunction of CD8+ T cells in ccRCC. We conclude that SPP1 may serve as a potential therapeutic target in ccRCC.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/40680256\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250718184744&amp;v=2.18.0.post9+e462414\">40680256<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-1146\">10.1158\/2326-6066.CIR-24-1146<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Jul 18. doi: 10.1158\/2326-6066.CIR-24-1146. Online ahead of print. ABSTRACT Tumor-associated macrophages (TAMs) are key regulators of tumor immunity. With advances in single-cell analyses, SPP1+ TAMs have been observed across multiple tumor sites. However, their clinical relevance and phenotypic characteristics in clear cell renal cell carcinoma (ccRCC) have not been comprehensively delineated. &#8230; <a title=\"SPP1+ Tumor-associated Macrophages Drive Immunotherapy Resistance via CD8+ T-Cell Dysfunction in Clear Cell Renal Cell Carcinoma\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/07\/19\/spp1-tumor-associated-macrophages-drive-immunotherapy-resistance-via-cd8-t-cell-dysfunction-in-clear-cell-renal-cell-carcinoma\/\" aria-label=\"Read more about SPP1+ Tumor-associated Macrophages Drive Immunotherapy Resistance via CD8+ T-Cell Dysfunction in Clear Cell Renal Cell Carcinoma\">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-38541","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\/38541","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=38541"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/38541\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=38541"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=38541"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=38541"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}