{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:07:13Z","timestamp":1784786833712,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"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 work aims to design and characterize a novel bifunctional small molecule that simultaneously targets PD-L1 and CD73 to enhance the therapeutic efficacy of tumor immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Multiple methodologies were integrated for compound screening and biological characterization, including computer-aided molecular docking, homogeneous time-resolved fluorescence (HTRF) binding assay, surface plasmon resonance (SPR), and PD-1\/PD-L1 NFAT reporter cell assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The lead compound CP-1 exhibited potent dual-target inhibitory activities. It blocked the PD-1\/PD-L1 interaction with an IC\n                      <jats:sub>50<\/jats:sub>\n                      of 10.27 nM and suppressed CD73 activity with an IC\n                      <jats:sub>50<\/jats:sub>\n                      of 300.2 nM. Molecular docking simulations revealed that CP-1 stably binds to the functional domains of PD-L1 and CD73 via specific non-covalent interactions. Cellular functional assays further demonstrated that CP-1 effectively restored T cell function in the PD-1\/PD-L1 reporter system, with an EC\n                      <jats:sub>50<\/jats:sub>\n                      of 0.9 \u03bcM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CP-1 exhibits balanced, dual-nanomolar inhibitory activity against PD-L1 and CD73 and displays potent immunomodulatory effects at the cellular level. It serves as a promising lead candidate for developing novel bifunctional agents to advance tumor immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1898645","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:41:10Z","timestamp":1784785270000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual-targeting CD73\/PD-L1 bifunctional inhibitor: a promising cancer immunotherapy strategy"],"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, 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