{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:29:44Z","timestamp":1771334984741,"version":"3.50.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T00:00:00Z","timestamp":1625529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014220","name":"National Natural Science Foundation of China-Henan Joint Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014220","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012659","name":"Foundation for Innovative Research Groups of the National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The widespread appearance of drug tolerance and the low efficiency of single treatment have severely affected the survival time of the patients with colorectal cancer. Exploring new treatment options and combined treatment strategies have become the key to improving the prognosis. The combination of immunotherapy and chemotherapy have shown good clinical expectations. Here, we studied the cooperative effects of chloroquine, an anti-malarial drug that is now widely used in anti-tumor research, and RNA interference (RNAi) targeting the immune checkpoint molecule Programmed Death-1 (PD-1) delivered with attenuated <jats:italic>Salmonella<\/jats:italic>. Our results show that chloroquine can not only significantly inhibit the survival of colon cancer cells and induce apoptosis, but also effectively inhibit cell invasion and migration. The results of <jats:italic>in vivo<\/jats:italic> experiments show that chloroquine can increase the expression of PD-1 in tumor tissues. Combining chloroquine and PD-1 siRNA can further inhibit the growth and metastases of colon cancer and induce apoptosis. The mechanism underlying this phenomenon is the occurrence of chloroquine-induced apoptosis and the effective immune response caused by the attenuated <jats:italic>Salmonella<\/jats:italic> carrying PD-1 siRNA. This study suggests that the combined application of PD-1-based immunotherapy and anti-cancer drugs has become a new expectation for clinical treatment of colorectal cancer.<\/jats:p>","DOI":"10.3389\/fimmu.2021.707991","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T07:40:34Z","timestamp":1625557234000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["PD-1-siRNA Delivered by Attenuated Salmonella Enhances the Antitumor Effect of Chloroquine in Colon Cancer"],"prefix":"10.3389","volume":"12","author":[{"given":"Shuya","family":"Lu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhui","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijie","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongbin","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuyang","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiesuo","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiateng","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/ans.16861","article-title":"Serum Carcinoembryonic Antigen Pre-Operative Level in Colorectal Cancer: Revisiting Risk Stratification","volume":"91","author":"Iacuzzo","year":"2021","journal-title":"ANZ J Surg"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer Statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/tri.13471","article-title":"Transplant Oncology: Assessment of Response and Tolerance to Systemic Chemotherapy for Metastatic Colorectal Cancer After Liver Transplantation -\u00a0A Retrospective Study","volume":"32","author":"Smedman","year":"2019","journal-title":"Transpl Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v24.i34.3834","article-title":"Drug Resistance and New Therapies in Colorectal Cancer","volume":"24","author":"Van der Jeught","year":"2018","journal-title":"World J Gastroenterol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0557-9","article-title":"Exosomal Wnt-Induced Dedifferentiation of Colorectal Cancer Cells Contributes to Chemotherapy Resistance","volume":"38","author":"Hu","year":"2019","journal-title":"Oncogene"},{"key":"B6","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/d41573-020-00010-6","article-title":"Improving Immunotherapy","volume":"19","author":"Crunkhorn","year":"2020","journal-title":"Nat Rev Drug Discov"},{"key":"B7","doi-asserted-by":"publisher","first-page":"S61","DOI":"10.1038\/d41586-017-08699-z","article-title":"Cancer Immunotherapy","volume":"552","author":"Bender","year":"2017","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41565-018-0328-3","article-title":"Surgical Wound Immunotherapy","volume":"14","author":"Liebers","year":"2019","journal-title":"Nat Nanotechnol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e000501","DOI":"10.1136\/esmoopen-2019-000501","article-title":"New Emerging Targets in Cancer Immunotherapy Beyond CTLA-4, PD-1 and PD-L1: Introducing an \u201cESMO Open - Cancer Horizons\u201d Series","volume":"4","author":"Lambertini","year":"2019","journal-title":"ESMO Open"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.117","article-title":"Exploiting CTLA-4, PD-1 and PD-L1 to Reactivate the Host Immune Response Against Cancer","volume":"108","author":"Quezada","year":"2013","journal-title":"Br J Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-17-0035","article-title":"Peptide Blocking of PD-1\/PD-L1 Interaction for Cancer Immunotherapy","volume":"6","author":"Li","year":"2018","journal-title":"Cancer Immunol Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99317","article-title":"Contribution of NK Cells to Immunotherapy Mediated by PD-1\/PD-L1 Blockade","volume":"128","author":"Hsu","year":"2018","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0512-0","article-title":"Inhibitory Receptors and Ligands Beyond PD-1, PD-L1 and CTLA-4: Breakthroughs or Backups","volume":"20","author":"Andrews","year":"2019","journal-title":"Nat Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e000798","DOI":"10.1136\/esmoopen-2020-000798","article-title":"European Medicines Agency Extension of Indication to Include the Combination Immunotherapy Cancer Drug Treatment With Nivolumab (Opdivo) and Ipilimumab (Yervoy) for Adults With Intermediate\/Poor-Risk Advanced Renal Cell Carcinoma","volume":"5","author":"Ali","year":"2020","journal-title":"ESMO Open"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-020-00525-1","article-title":"Keytruda and PD-L1: A Real-World Example of Co-development of a Drug with a Predictive Biomarker","volume":"23","author":"Emancipator","year":"2020","journal-title":"AAPS J"},{"key":"B16","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1002\/med.21530","article-title":"Immunomodulators Targeting the PD-1\/PD-L1 Protein-Protein Interaction: From Antibodies to Small Molecules","volume":"39","author":"Yang","year":"2019","journal-title":"Med Res Rev"},{"key":"B17","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1038\/s41419-019-1418-3","article-title":"PD-1-siRNA Delivered by Attenuated Salmonella Enhances the Antimelanoma Effect of Pimozide","volume":"10","author":"Zhao","year":"2019","journal-title":"Cell Death Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.11.024","article-title":"Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy","volume":"44","author":"Pfirschke","year":"2016","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2016.05.021","article-title":"Radiation Effects on the Tumor Microenvironment: Implications for Nanomedicine Delivery","volume":"109","author":"Stapleton","year":"2017","journal-title":"Adv Drug Delivery Rev"},{"key":"B20","doi-asserted-by":"publisher","first-page":"47","DOI":"10.5694\/mja2.12046","article-title":"Radiotherapy and Immunotherapy: A Synergistic Effect in Cancer Care","volume":"210","author":"Turgeon","year":"2019","journal-title":"Med J Aust"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0372-x","article-title":"Mechanisms of Action of Hydroxychloroquine and Chloroquine: Implications for Rheumatology","volume":"16","author":"Schrezenmeier","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-015-0239-y","article-title":"Therapy And Pharmacological Properties Of Hydroxychloroquine And Chloroquine In Treatment Of Systemic Lupus Erythematosus, Rheumatoid Arthritis And Related Diseases","volume":"23","author":"Rainsford","year":"2015","journal-title":"Inflammopharmacology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-010-8243-x","article-title":"Hydroxychloroquine: From Malaria to Autoimmunity","volume":"42","author":"Ben-Zvi","year":"2012","journal-title":"Clin Rev Allergy Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3390\/microorganisms8010085","article-title":"The Use of Antimalarial Drugs Against Viral Infection","volume":"8","author":"D\u2019Alessandro","year":"2020","journal-title":"Microorganisms"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/1440-1681.12581","article-title":"Molecular Mechanisms for Tumour Resistance to Chemotherapy","volume":"43","author":"Pan","year":"2016","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202002922","article-title":"AZD9291 Resistance Reversal Activity of a pH-Sensitive Nanocarrier Dual-Loaded With Chloroquine and FGFR1 Inhibitor in NSCLC","volume":"8","author":"Gu","year":"2021","journal-title":"Adv Sci (Weinh)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.53024","article-title":"Saikosaponin-D Increases Radiation-Induced Apoptosis of Hepatoma Cells by Promoting Autophagy via Inhibiting mTOR Phosphorylation","volume":"18","author":"Wang","year":"2021","journal-title":"Int J Med Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-020-04100-5","article-title":"Inhibition of Autophagy by Chloroquine Enhances the Antitumor Activity of Gemcitabine for Gallbladder Cancer","volume":"86","author":"Wang","year":"2020","journal-title":"Cancer Chemother Pharmacol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.cbi.2014.04.007","article-title":"Chloroquine Synergizes Sunitinib Cytotoxicity via Modulating Autophagic, Apoptotic and Angiogenic Machineries","volume":"217","author":"Abdel-Aziz","year":"2014","journal-title":"Chem Biol Interact"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0611","article-title":"Aspirin Use and the Risk of Cancer","volume":"5","author":"Skelin","year":"2019","journal-title":"JAMA Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/apt.16071","article-title":"Editorial: The Microbiome, Aspirin and Colorectal Cancer","volume":"52","author":"O\u2019Grady","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-14-0284","article-title":"Metformin, Cancer and Glucose Metabolism","volume":"21","author":"Salani","year":"2014","journal-title":"Endocr Relat Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/nrgastro.2015.9","article-title":"Gastric Cancer. Metformin Improves Survival and Recurrence Rate in Patients With Diabetes and Gastric Cancer","volume":"12","author":"Greenhill","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.coi.2020.07.005","article-title":"The Host Targeting Effect of Chloroquine in Malaria","volume":"66","author":"Coban","year":"2020","journal-title":"Curr Opin Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-015-0239-y","article-title":"Therapy and Pharmacological Properties of Hydroxychloroquine and Chloroquine in Treatment of Systemic Lupus Erythematosus, Rheumatoid Arthritis and Related Diseases","volume":"23","author":"Rainsford","year":"2015","journal-title":"Inflammopharmacology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1158\/0008-5472.CAN-12-2464","article-title":"Chloroquine in Cancer Therapy: A Double-Edged Sword of Autophagy","volume":"73","author":"Kimura","year":"2013","journal-title":"Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0706","article-title":"PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer","volume":"9","author":"Rebecca","year":"2019","journal-title":"Cancer Discovery"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-019-05381-y","article-title":"A Randomized, Double-Blind, Window of Opportunity Trial Evaluating the Effects of Chloroquine in Breast Cancer Patients","volume":"178","author":"Arnaout","year":"2019","journal-title":"Breast Cancer Res Treat"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2019.02.009","article-title":"Core-Matched Nanoassemblies for Targeted Co-Delivery of Chemotherapy and Photosensitizer to Treat Drug-Resistant Cancer","volume":"88","author":"Jiang","year":"2019","journal-title":"Acta Biomater"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.3390\/ijms18091903","article-title":"Roles of Long Noncoding RNAs in Recurrence and Metastasis of Radiotherapy-Resistant Cancer Stem Cells","volume":"18","author":"Chi","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy089","article-title":"Combined Immunotherapy Encompassing Intratumoral Poly-ICLC,  Dendritic-Cell Vaccination and Radiotherapy in Advanced Cancer Patients","volume":"29","author":"Rodriguez-Ruiz","year":"2018","journal-title":"Ann Oncol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S175614","article-title":"Colorectal Cancer Combination Therapy Using Drug and Gene Co-Delivered, Targeted Poly(Ethylene Glycol)-Epsilon-Poly(Caprolactone) Nanocarriers","volume":"12","author":"Wang","year":"2018","journal-title":"Drug Des Devel Ther"},{"key":"B43","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1038\/nrd.2016.145","article-title":"Cancer: Combination Therapy for Lung Cancer","volume":"15","author":"Crunkhorn","year":"2016","journal-title":"Nat Rev Drug Discovery"},{"key":"B44","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.ccell.2018.03.018","article-title":"Genomic Features of Response to Combination Immunotherapy in Patients With Advanced Non-Small-Cell Lung Cancer","volume":"33","author":"Hellmann","year":"2018","journal-title":"Cancer Cell"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-3338","article-title":"Landscape of Combination Immunotherapy and Targeted Therapy to Improve Cancer Management","volume":"77","author":"Colli","year":"2017","journal-title":"Cancer Res"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e13268","DOI":"10.1111\/ecc.13268","article-title":"Targeting Immune Checkpoints: Building Better Therapeutic Puzzle in Pancreatic Cancer Combination Therapy","volume":"29","author":"Abdkarimi","year":"2020","journal-title":"Eur J Cancer Care (Engl)"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3323","article-title":"Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer: Combination Therapy in the First-Line Setting","volume":"26","author":"Aggen","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B48","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s13045-019-0779-5","article-title":"Immune Checkpoint Inhibitors of PD-L1 as Cancer Therapeutics","volume":"12","author":"Akinleye","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.624759","article-title":"Use of Salmonella Bacteria in Cancer Therapy: Direct, Drug Delivery and Combination Approaches","volume":"11","author":"Badie","year":"2021","journal-title":"Front Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.10.033","article-title":"Targeted Cancer Immunotherapy With Genetically Engineered Oncolytic Salmonella Typhimurium","volume":"469","author":"Guo","year":"2020","journal-title":"Cancer Lett"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.707991\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T07:40:39Z","timestamp":1625557239000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.707991\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,6]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2021.707991"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.707991","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,6]]},"article-number":"707991"}}