{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:50:35Z","timestamp":1791474635996,"version":"4.3.4"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"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:p>The SIRP\u03b1Fc fusion protein can block the immunosuppressive CD47-SIRP\u03b1 signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide \u201cTKKTLRT\u201d is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRP\u03b1Fc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT\u2013SIRP\u03b1Fc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT\u2013SIRP\u03b1Fc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. <jats:italic>In vivo<\/jats:italic> distribution experiments showed that CBD\u2013SIRP\u03b1Fc accumulated in tumor tissue more effectively compared to unmodified SIRP\u03b1Fc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD\u2013SIRP\u03b1Fc presented more stable and effective antitumor efficacy than SIRP\u03b1Fc, along with significantly increased CD11b<jats:sup>+<\/jats:sup>F4\/80<jats:sup>+<\/jats:sup> macrophages especially MHC II<jats:sup>+<\/jats:sup> M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRP\u03b1Fc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD\u2013SIRP\u03b1Fc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.<\/jats:p>","DOI":"10.3389\/fimmu.2022.845217","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T05:03:42Z","timestamp":1648616622000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["A SIRP\u03b1Fc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung 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