{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:16:14Z","timestamp":1788419774921,"version":"build-2803163510"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"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>Objectives<\/jats:title>\n                    <jats:p>This study aims to discover and characterize novel D(+)-biotin-conjugated PD-L1 inhibitors for precision tumor-targeted cancer immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Integrated strategies, including computer-aided molecular simulation, antiproliferative activity (CCK8) assay, surface plasmon resonance (SPR), pharmacokinetic evaluation, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      antitumor efficacy assessment, were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compound SW-1 showed potent and selective inhibitory activity against PD-1\/PD-L1 interaction with an IC\n                      <jats:sub>50<\/jats:sub>\n                      of 5.6 nM, and high binding affinity to both human and murine PD-L1. Molecular docking and molecular dynamics simulations verified stable binding of SW-1 to the PD-L1 dimer interface with key intermolecular interactions. Pharmacokinetic studies in rats revealed favorable systemic exposure and a suitable half-life for\n                      <jats:italic>in vivo<\/jats:italic>\n                      application. In the B16-F10 melanoma mouse model, SW-1 achieved a more potent tumor growth inhibition (TGI\u00a0=\u00a064.9%) than the PD-L1 antibody (TGI\u00a0=\u00a044.2%), effectively promoted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration into the tumor microenvironment, and maintained favorable\n                      <jats:italic>in vivo<\/jats:italic>\n                      safety without obvious body weight loss.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SW-1, as a highly potent biotin-conjugated PD-L1 small-molecule inhibitor, exhibits outstanding target activity, favorable pharmacokinetic properties, potent antitumor efficacy, and high safety. These results highlight SW-1 as a promising lead candidate for further development in precision tumor-targeted immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1879839","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:41:53Z","timestamp":1788417713000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rational design of D(+)-biotin-conjugated resorcinol dibenzyl ethers as tumor-targeted PD-L1 inhibitors for precision cancer immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing-Jing","family":"Du","sequence":"first","affiliation":[{"name":"Hubei Provincial Key Laboratory of Occurrence and Intervention of Kidney Diseases, Hubei Provincial Engineering Research Center of Immunotherapy Drugs for Renal Tumors, Hubei Polytechnic University, School of Medicine","place":["Huangshi, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongling","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory of Occurrence and Intervention of Kidney Diseases, Hubei Provincial Engineering Research Center of Immunotherapy Drugs for Renal Tumors, Hubei Polytechnic University, School of Medicine","place":["Huangshi, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory of Occurrence and Intervention of Kidney Diseases, Hubei Provincial Engineering Research Center of Immunotherapy Drugs for Renal Tumors, Hubei Polytechnic University, School of Medicine","place":["Huangshi, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Huangshi Central Hospital","place":["Huangshi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2015.03.004","article-title":"Immune evasion in cancer: Mechanistic basis and therapeutic strategies","volume":"35","author":"Vinay","year":"2015","journal-title":"Semin Cancer Biol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s12916-016-0623-5","article-title":"Cancer immunotherapy: the beginning of the end of cancer","volume":"14","author":"Farkona","year":"2016","journal-title":"BMC Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00315","article-title":"Immuno-Oncology: Emerging targets and combination therapies","volume":"8","author":"Marshall","year":"2018","journal-title":"Front Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1097\/bs9.0000000000000149","article-title":"PD-L1: expression regulation","volume":"5","author":"Zhou","year":"2023","journal-title":"Blood Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02022","article-title":"PD-L1 distribution and perspective for cancer immunotherapy-blockade, knockdown, or inhibition","volume":"10","author":"Wu","year":"2019","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41401-020-0366-x","article-title":"Small molecule inhibitors targeting the PD-1\/PD-L1 signaling pathway","volume":"42","author":"Wu","year":"2021","journal-title":"Acta Pharmacol Sin"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.108036","article-title":"Beyond peptides: Unveiling the design strategies, structure activity correlations and protein-ligand interactions of small molecule inhibitors against PD-1\/PD-L1","volume":"154","author":"Sasmal","year":"2025","journal-title":"Bioorg Chem"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2022.117001","article-title":"Biphenyl-based small molecule inhibitors: Novel cancer immunotherapeutic agents targeting PD-1\/PD-L1 interaction","volume":"73","author":"Sasmal","year":"2022","journal-title":"Bioorg Med Chem"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.21147\/j.issn.1000-9604.2018.02.01","article-title":"Future of anti-PD-1\/PD-L1 applications: Combinations with other therapeutic regimens","volume":"30","author":"Song","year":"2018","journal-title":"Chin J Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.7555\/JBR.31.20160168","article-title":"Immune checkpoint inhibitors in cancer therapy","volume":"32","author":"Webb","year":"2018","journal-title":"J BioMed Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2012.04224.x","article-title":"Role of the PD-1 pathway in the immune response","volume":"12","author":"Riella","year":"2012","journal-title":"Am J Transplant"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.117212","article-title":"Recent advances in developing targeted protein degraders","volume":"284","author":"Cheng","year":"2024","journal-title":"Eur J Med Chem"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117289","article-title":"Research progress in bifunctional small molecules for cancer immunotherapy","volume":"286","author":"Cheng","year":"2025","journal-title":"Eur J Med Chem"},{"key":"B14","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/978-981-15-3266-5_3","article-title":"Roles of PD-1\/PD-L1 pathway: Signaling, cancer, and beyond","volume":"1248","author":"Ai","year":"2020","journal-title":"Adv Exp Med Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01422","article-title":"Design, synthesis, and pharmacological evaluation of biaryl-containing PD-1\/PD-L1 interaction inhibitors bearing a unique difluoromethyleneoxy linkage","volume":"64","author":"Song","year":"2021","journal-title":"J Med Chem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02362","article-title":"Discovery of highly potent small-molecule PD-1\/PD-L1 inhibitors with a novel scaffold for cancer immunotherapy","volume":"67","author":"Xu","year":"2024","journal-title":"J Med Chem"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02143","article-title":"Reducing PD-L1 expression by degraders and downregulators as a novel strategy to target the PD-1\/PD-L1 pathway","volume":"67","author":"Wang","year":"2024","journal-title":"J Med Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00479","article-title":"Discovery of novel d-(+)-biotin-conjugated resorcinol dibenzyl ether-based PD-L1 inhibitors for targeted cancer immunotherapy","volume":"66","author":"Ding","year":"2023","journal-title":"J Med Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1039\/d0sc01973a","article-title":"Probing biotin receptors in cancer cells with rationally designed fluorogenic squaraine dimers","volume":"11","author":"Fam","year":"2020","journal-title":"Chem Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2025.2554896","article-title":"Biotin-mediated drug delivery: does the biotin transporter mediate uptake of biotin conjugates","volume":"40","author":"Tripathi","year":"2025","journal-title":"J Enzyme Inhib Med Chem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2012.10.047","article-title":"Biotin uptake by T47D breast cancer cells: functional and molecular evidence of sodium-dependent multivitamin transporter (SMVT)","volume":"441","author":"Vadlapudi","year":"2013","journal-title":"Int J Pharm"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02231","article-title":"Discovery of novel heterotricyclic compounds as DNA-dependent protein kinase (DNA-PK) inhibitors with enhanced chemosensitivity, oral bioavailability, and the ability to potentiate cancer immunotherapy","volume":"67","author":"Cheng","year":"2024","journal-title":"J Med Chem"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c03630","article-title":"Discovery of novel heterotetracyclic DNA-dependent protein kinase (DNA-PK) inhibitors with improved oral bioavailability and potent cancer immunotherapy-potentiating activity","volume":"69","author":"Guan","year":"2026","journal-title":"J Med Chem"},{"key":"B24","doi-asserted-by":"publisher","first-page":"S2090","DOI":"10.1016\/j.jare.2025.11.042","article-title":"Spop-binding bifunctional degraders: a novel approach for cancer immunotherapy","author":"Cheng","year":"2025","journal-title":"J Adv Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1879839\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:41:54Z","timestamp":1788417714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1879839\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":24,"alternative-id":["10.3389\/fimmu.2026.1879839"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1879839","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"article-number":"1879839"}}