{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:18:33Z","timestamp":1788218313827,"version":"build-2803163510"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"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":"publisher","award":["82273109"],"award-info":[{"award-number":["82273109"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20232BAB206100"],"award-info":[{"award-number":["20232BAB206100"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Programmed death-ligand 1 (PD-L1) is a key mediator of tumor immune evasion, but the protein networks governing its post-translational regulation remain incompletely understood. Here, we used PhastID-based proximity labeling to map the PD-L1 proximal proteome and integrated these data with pan-cancer proteomics and immunohistochemical analysis of clinical tumor samples. We found that C-terminal-proximal proteins were enriched in protein degradation, ER-associated quality control, and immune-related pathways, whereas N-terminal-proximal proteins were mainly associated with protein localization and intracellular transport. Integrated analysis identified CAND1, TXN, and FBXO2 as candidate PD-L1 regulators. Knockdown of CAND1, TXN, or FBXO2 reduced PD-L1 protein expression in cancer cells. Mechanistically, CAND1 interacted with PD-L1 and was detected in a complex containing PD-L1 and FBXO22. CAND1 depletion promoted K48-linked ubiquitination and degradation of PD-L1, while deletion of the PD-L1 intracellular domain or mutation of K271 and K281 attenuated PD-L1 ubiquitination. Functionally, CAND1 knockdown enhanced T cell-mediated tumor cell killing, and elevated CAND1 expression was associated with an immunosuppressive tumor microenvironment. Together, our findings define the PD-L1 proximal proteomic landscape and identify CAND1-mediated regulation of PD-L1 stability as a potential mechanism of tumor immune escape.<\/jats:p>","DOI":"10.1021\/acsomega.6c06622","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T20:02:04Z","timestamp":1786651324000},"page":"50389-50405","source":"Crossref","is-referenced-by-count":0,"title":["Proximal Proteomics\nReveals Potential Regulators of\nProgrammed Death-Ligand 1 in Human Cancer"],"prefix":"10.1021","volume":"11","author":[{"given":"Fujin","family":"Shi","sequence":"first","affiliation":[{"name":"Jiangxi Medical College, Nanchang University , , ,","place":["Nanchang, China, 330006"]},{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danya","family":"Liu","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxiong","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangxi Medical College, Nanchang University , , ,","place":["Nanchang, China, 330006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangxi Medical College, Nanchang University , , ,","place":["Nanchang, China, 330006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris Zhiyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuli","family":"Li","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University Cancer Center , , ,","place":["Guangzhou, China, 510060"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3359-8692","authenticated-orcid":true,"given":"Qiu-Hong","family":"Tian","sequence":"additional","affiliation":[{"name":"Jiangxi Medical College, Nanchang University , , ,","place":["Nanchang, China, 330006"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"9","key":"2026083119120225600_cit1","doi-asserted-by":"publisher","first-page":"3384","DOI":"10.1172\/JCI80011","article-title":"Anti-PD-1\/PD-L1\ntherapy of human cancer: past, present, and future","volume":"125","author":"Chen","year":"2015","journal-title":"J. Clin. Invest."},{"issue":"10","key":"2026083119120225600_cit2","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1158\/1078-0432.CCR-16-0224","article-title":"Dual Faces\nof IFN\u03b3 in Cancer\nProgression: A Role of PD-L1 Induction in the Determination of Pro-\nand Antitumor Immunity","volume":"22","author":"Mandai","year":"2016","journal-title":"Clin. Cancer Res."},{"issue":"10","key":"2026083119120225600_cit3","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1158\/2326-6066.CIR-17-0537","article-title":"Programmed\nCell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation\nand Activation","volume":"6","author":"Hartley","year":"2018","journal-title":"Cancer Immunol. Res."},{"issue":"3","key":"2026083119120225600_cit4","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.immuni.2018.03.014","article-title":"Regulation and Function of the PD-L1\nCheckpoint","volume":"48","author":"Sun","year":"2018","journal-title":"Immunity"},{"issue":"2","key":"2026083119120225600_cit5","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1158\/1078-0432.CCR-18-2484","article-title":"Anti-PD-1 Antibody SHR-1210 Combined\nwith Apatinib for Advanced Hepatocellular\nCarcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label,\nDose Escalation and Expansion Study","volume":"25","author":"Xu","year":"2019","journal-title":"Clin. Cancer\nRes."},{"issue":"13","key":"2026083119120225600_cit6","doi-asserted-by":"publisher","first-page":"2332","DOI":"10.1016\/j.molcel.2023.05.034","article-title":"Structural\nand mechanistic insights into the CAND1-mediated SCF substrate receptor\nexchange","volume":"83","author":"Shaaban","year":"2023","journal-title":"Mol. Cell."},{"issue":"12","key":"2026083119120225600_cit7","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007766","article-title":"ASCC3 promotes\nthe immunosuppression and progression of non-small cell lung cancer\nby impairing the type I interferon response via CAND1-mediated ubiquitination\ninhibition of STAT3","volume":"11","author":"Ao","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"2026083119120225600_cit8","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215692","article-title":"GSTM3 deficiency\nimpedes\nDNA mismatch repair to promote gastric tumorigenesis via CAND1\/NRF2-KEAP1\nsignaling","volume":"538","author":"Chen","year":"2022","journal-title":"Cancer Lett."},{"issue":"1","key":"2026083119120225600_cit9","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.cell.2013.02.024","article-title":"Cand1 promotes\nassembly of new SCF complexes through dynamic exchange of F box proteins","volume":"153","author":"Pierce","year":"2013","journal-title":"Cell"},{"issue":"5","key":"2026083119120225600_cit10","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s41422-024-00938-z","article-title":"The rapid proximity labeling system\nPhastID identifies\nATP6AP1 as an unconventional GEF for Rheb","volume":"34","author":"Feng","year":"2024","journal-title":"Cell\nRes."},{"issue":"5","key":"2026083119120225600_cit11","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal\nsample preparation\nmethod for proteome analysis","volume":"6","author":"Wis\u0301niewski","year":"2009","journal-title":"Nat. Methods"},{"key":"2026083119120225600_cit12","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-7-191","article-title":"STEM: a tool\nfor the analysis of short time series\ngene expression data","volume":"7","author":"Ernst","year":"2006","journal-title":"BMC Bioinf."},{"issue":"3","key":"2026083119120225600_cit13","doi-asserted-by":"publisher","DOI":"10.1002\/imt2.36","article-title":"Sangerbox: A comprehensive, interaction-friendly clinical\nbioinformatics analysis platform","volume":"1","author":"Shen","year":"2022","journal-title":"iMeta"},{"issue":"4","key":"2026083119120225600_cit14","doi-asserted-by":"publisher","DOI":"10.1002\/imt2.215","article-title":"BioLadder:\nA bioinformatic platform primarily focused on proteomic data analysis","volume":"3","author":"Zhang","year":"2024","journal-title":"iMeta"},{"issue":"6","key":"2026083119120225600_cit15","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1021\/acs.jproteome.4c00124","article-title":"Pan-Cancer\nProteomics Analysis Reveals Wiskott-Aldrich Syndrome Protein as a\nPotential Regulator of Programmed Death-Ligand 1","volume":"23","author":"Hu","year":"2024","journal-title":"J. Proteome Res."},{"issue":"4","key":"2026083119120225600_cit16","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/s41416-025-03068-4","article-title":"Proteomics\nanalysis and immune profiling\nreveal regulators of PD-L1 in oesophageal squamous cell carcinoma","volume":"133","author":"Li","year":"2025","journal-title":"Br. J. Cancer"},{"issue":"1","key":"2026083119120225600_cit17","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-021-01489-2","article-title":"Combination strategies with PD-1\/PD-L1\nblockade: current advances\nand future directions","volume":"21","author":"Yi","year":"2022","journal-title":"Mol. Cancer"},{"issue":"6","key":"2026083119120225600_cit18","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/s41571-021-00473-5","article-title":"PD-L1 as a biomarker\nof response to immune-checkpoint\ninhibitors","volume":"18","author":"Doroshow","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"issue":"23","key":"2026083119120225600_cit19","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1056\/NEJMoa1809064","article-title":"First-Line\nAtezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung\nCancer","volume":"379","author":"Horn","year":"2018","journal-title":"N. Engl. J. Med."},{"issue":"16","key":"2026083119120225600_cit20","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1200\/JCO.2017.76.2229","article-title":"Safety and Clinical Activity of Pembrolizumab\nand Multisite Stereotactic Body Radiotherapy in Patients With Advanced\nSolid Tumors","volume":"36","author":"Luke","year":"2018","journal-title":"J. Clin. Oncol."},{"issue":"6","key":"2026083119120225600_cit21","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002195","article-title":"STING activation normalizes\nthe intraperitoneal vascular-immune microenvironment and suppresses\nperitoneal carcinomatosis of colon cancer","volume":"9","author":"Lee","year":"2021","journal-title":"J.\nImmunother. Cancer"},{"issue":"6529","key":"2026083119120225600_cit22","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1126\/science.abf3363","article-title":"Fecal microbiota transplant overcomes resistance to\nanti-PD-1 therapy in melanoma patients","volume":"371","author":"Davar","year":"2021","journal-title":"Science"},{"issue":"17","key":"2026083119120225600_cit23","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201806957","article-title":"A Dual-Bioresponsive\nDrug-Delivery Depot for Combination of Epigenetic Modulation and Immune\nCheckpoint Blockade","volume":"31","author":"Ruan","year":"2019","journal-title":"Adv. Mater."},{"issue":"2","key":"2026083119120225600_cit24","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.cell.2020.08.053","article-title":"A Phase Ib\nTrial of Personalized\nNeoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma,\nNon-small Cell Lung Cancer, or Bladder Cancer","volume":"183","author":"Ott","year":"2020","journal-title":"Cell"},{"issue":"1","key":"2026083119120225600_cit25","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-019-0721-x","article-title":"Activating\ncGAS-STING pathway for the optimal effect of cancer immunotherapy","volume":"12","author":"Li","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"2026083119120225600_cit26","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2021.106002","article-title":"The biology of combination immunotherapy\nin recurrent metastatic\nhead and neck cancer","volume":"136","author":"Yuan","year":"2021","journal-title":"Int. J. Biochem. Cell\nBiol."},{"issue":"1","key":"2026083119120225600_cit27","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01164-5","article-title":"Combination\nstrategies to maximize\nthe benefits of cancer immunotherapy","volume":"14","author":"Zhu","year":"2021","journal-title":"J. Hematol.\nOncol."},{"issue":"1","key":"2026083119120225600_cit28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016071","article-title":"Regulation of cullin\nRING E3 ubiquitin ligases by CAND1 in vivo","volume":"6","author":"Chua","year":"2011","journal-title":"PLoS One"},{"issue":"4","key":"2026083119120225600_cit29","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1128\/MCB.26.4.1235-1244.2006","article-title":"CAND1-mediated substrate adaptor\nrecycling is required\nfor efficient repression of Nrf2 by Keap1","volume":"26","author":"Lo","year":"2006","journal-title":"Mol.\nCell. Biol."},{"issue":"18","key":"2026083119120225600_cit30","doi-asserted-by":"publisher","first-page":"15905","DOI":"10.1074\/jbc.M213070200","article-title":"TIP120A associates\nwith cullins and modulates ubiquitin\nligase activity","volume":"278","author":"Min","year":"2003","journal-title":"J. Biol. Chem."},{"issue":"4","key":"2026083119120225600_cit31","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nrc3700","article-title":"Roles of F-box proteins in cancer","volume":"14","author":"Wang","year":"2014","journal-title":"Nat. Rev. Cancer"},{"issue":"12","key":"2026083119120225600_cit32","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1038\/nrd4432","article-title":"SCF ubiquitin\nligase-targeted therapies","volume":"13","author":"Skaar","year":"2014","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"47","key":"2026083119120225600_cit33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2112674118","article-title":"The ubiquitin\nE3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA\ndamage","volume":"118","author":"De","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"7734","key":"2026083119120225600_cit34","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/s41586-018-0756-0","article-title":"FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity\nof T cells","volume":"564","author":"Meng","year":"2018","journal-title":"Nature"},{"issue":"5","key":"2026083119120225600_cit35","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04892-9","article-title":"FBXO2 targets glycosylated SUN2 for\nubiquitination and degradation\nto promote ovarian cancer development","volume":"13","author":"Ji","year":"2022","journal-title":"Cell\nDeath Dis."},{"issue":"2","key":"2026083119120225600_cit36","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1093\/neuonc\/noac169","article-title":"Quantitative proteomic landscapes of primary and recurrent glioblastoma\nreveal a protumorigeneic role for FBXO2-dependent glioma-microenvironment\ninteractions","volume":"25","author":"Buehler","year":"2023","journal-title":"Neuro-Oncology"},{"issue":"1","key":"2026083119120225600_cit37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22467-8","article-title":"ARIH1 signaling\npromotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation","volume":"12","author":"Wu","year":"2021","journal-title":"Nat. Commun."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c06622","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/50389\/66535227\/acsomega.6c06622.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/50389\/66535227\/acsomega.6c06622.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:12:08Z","timestamp":1788217928000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/33\/50389\/5254796\/Proximal-Proteomics-Reveals-Potential-Regulators"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":37,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,13]]},"published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c06622","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}