{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:25:28Z","timestamp":1787030728284,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81773621"],"award-info":[{"award-number":["81773621"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82073751"],"award-info":[{"award-number":["82073751"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["81773621"],"award-info":[{"award-number":["81773621"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82073751"],"award-info":[{"award-number":["82073751"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Facility for Translational Medicine (Shanghai) Open Research Program Foundation","award":["TMSK-2020-131"],"award-info":[{"award-number":["TMSK-2020-131"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: The efficacy of chemotherapy in triple-negative breast cancer (TNBC) is limited by intrinsic resistance and the tumor microenvironment (TME). Accumulating evidence reveals a mechanistic connection between programmed death-ligand 1 (PD-L1) and c-x-c motif chemokine receptor 4 (CXCR4), which dominate stroma barriers, immune escape, and cancer metastasis. Earlier studies have shown that dual suppression of c-x-c motif ligand 12 (CXCL12)\/CXCR4 and programmed cell death-1 (PD-1)\/PD-L1 pathways regulates extracellular matrix (ECM) deposition, activation of cancer-associated fibroblasts (CAFs), and epithelial\u2013mesenchymal transition (EMT) of pancreatic cancer cells. Methods: We combined BsNb PX4, a bispecific nanobody targeting PD-L1 and CXCR4, with paclitaxel or gemcitabine in multiple tumor cell lines and human peripheral blood mononuclear cell (hPBMC)-reconstituted xenograft mouse models. Antitumor activity was assessed by CCK-8, flow cytometry, and ELISA, and immune cell infiltration and TME remodeling were examined by immunofluorescence, immunohistochemistry, cytokine assays, and RNA-seq. Results: In MDA-MB-231 cells, BsNb PX4 synergistically enhanced paclitaxel-induced growth inhibition and apoptosis via G2\/M cycle arrest. This combinatorial strategy profoundly remodeled tumor immunity by expanding CD8+ T cells and depleting Foxp3+ CD4+ regulatory T cells (Tregs), while concurrently restoring T-cell cytotoxicity and skewing the cytokine balance toward an antitumor state, with elevated IFN-\u03b3 and reduced TGF-\u03b21. Notably, compared with paclitaxel monotherapy, the combination significantly elevated intratumoral CD8+ T-cell infiltration, decreased Treg abundance, and exerted robust inhibitory effects on tumor growth and metastasis in humanized TNBC xenografts. Conclusions: These findings reveal that dual blockade of PD-L1 and CXCR4 acts synergistically with chemotherapy by triggering tumor cell apoptotic effects and reversing the immunosuppressive microenvironment, thereby emerging as a promising therapeutic strategy for TNBC.<\/jats:p>","DOI":"10.3390\/ph19081288","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T08:05:41Z","timestamp":1786953941000},"page":"1288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A CXCR4\/PD-L1 Bispecific Nanobody Engineered for Tumor Microenvironment Retention Mediates Sustained Synergy with Chemotherapy via Remodeling Immunity in TNBC"],"prefix":"10.3390","volume":"19","author":[{"given":"Shuyi","family":"Xu","sequence":"first","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Hu","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Li","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1672-4455","authenticated-orcid":false,"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pameila","family":"Paerhati","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Bao","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Bian","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6782-2023","authenticated-orcid":false,"given":"Jianwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"},{"name":"BioKu Biopharmaceuticals Co., Ltd., Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8367-3478","authenticated-orcid":false,"given":"Mingyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e000357","DOI":"10.1136\/esmoopen-2018-000357","article-title":"How shall we treat early triple-negative breast cancer (TNBC): From the current standard to upcoming immuno-molecular strategies","volume":"3","author":"Park","year":"2018","journal-title":"ESMO Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s13045-022-01341-0","article-title":"Recent advances in therapeutic strategies for triple-negative breast cancer","volume":"15","author":"Li","year":"2022","journal-title":"J. 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