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Tumor","award":["82074286"],"award-info":[{"award-number":["82074286"]}]},{"name":"Open Fund Project of the NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor","award":["BK20191428"],"award-info":[{"award-number":["BK20191428"]}]},{"name":"Open Fund Project of the NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor","award":["SH2022025"],"award-info":[{"award-number":["SH2022025"]}]},{"name":"Open Fund Project of the NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor","award":["NHCDP2024005"],"award-info":[{"award-number":["NHCDP2024005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Monoclonal antibodies targeting the PD-1\/PD-L1 immune checkpoint have achieved clinical success but face drawbacks such as poor oral bioavailability, limited tumor penetration, and immune-related adverse events. Small-molecule inhibitors present a promising alternative that may overcome these challenges. Methods: Here, an integrated computational framework combining ligand-based pharmacophore modeling and structure-based molecular docking was utilized to screen a comprehensive library consisting of traditional Chinese medicine-derived compounds and clinically approved drugs. The binding affinity between identified candidate compounds and PD-L1 was quantitatively assessed using bio-layer interferometry (BLI). In vitro cytotoxicity assays were conducted on A549 human lung carcinoma and LLC mouse lung carcinoma cell lines. In vivo antitumor efficacy was evaluated in LLC tumor-bearing mice through measurement of tumor growth inhibition, serum cytokine levels (IFN-\u03b3 and IL-4) by ELISA, and expression levels of IFN-\u03b3 and granzyme B (GZMB) within tumor tissues via immunohistochemistry. Results: In vitro, anidulafungin exhibited anti-tumor effects against both human lung cancer A549 cells and mouse Lewis lung carcinoma (LLC) tumor cells, with IC50 values of 170.6 \u00b5g\/mL and 160.9 \u00b5g\/mL, respectively. The BLI analysis revealed a dissociation constant (KD) of 76.9 \u03bcM, indicating a high affinity of anidulafungin for PD-L1. In vivo, anidulafungin significantly increased serum levels of IFN-\u03b3 and IL-4 in tumor-bearing mice and elevated expression of IFN-\u03b3 and granzyme B (GZMB) in tumor tissues, confirming its immune-mediated anti-tumor effects. Conclusions: Anidulafungin represents a promising small-molecule PD-L1 inhibitor, demonstrating significant anti-tumor potential via immune activation and highlighting the feasibility of repurposing approved drugs for cancer immunotherapy.<\/jats:p>","DOI":"10.3390\/ph18081209","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T14:24:28Z","timestamp":1755267868000},"page":"1209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery of Small-Molecule PD-L1 Inhibitors via Virtual Screening and Their Immune-Mediated Anti-Tumor Effects"],"prefix":"10.3390","volume":"18","author":[{"given":"Chunlai","family":"Feng","sequence":"first","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"},{"name":"NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Ge","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1809-8857","authenticated-orcid":false,"given":"Siqi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3602-9219","authenticated-orcid":false,"given":"Qiying","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hangyu","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjie","family":"Rui","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dai, X., Wang, K., Chen, H., Huang, X., and Feng, Z. 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