{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:39:38Z","timestamp":1792798778518,"version":"4.5.0"},"reference-count":44,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T00:00:00Z","timestamp":1584057600000},"content-version":"unspecified","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"the Major Science and Technology Innovation Program of Shanghai Municipal Education Commission","award":["2019-01-07-00-01-E00059"],"award-info":[{"award-number":["2019-01-07-00-01-E00059"]}],"id":[{"id":"https:\/\/ror.org\/05tewj457","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009018","name":"Shanghai Municipal Human Resources and Social Security Bureau","doi-asserted-by":"publisher","award":["2018060"],"award-info":[{"award-number":["2018060"]}],"id":[{"id":"10.13039\/501100009018","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Municipality Health Commission","award":["2017YQ0059"],"award-info":[{"award-number":["2017YQ0059"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81630086"],"award-info":[{"award-number":["81630086"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81973078"],"award-info":[{"award-number":["81973078"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004921","name":"Shanghai Jiao Tong University","doi-asserted-by":"publisher","award":["YG2017MS85"],"award-info":[{"award-number":["YG2017MS85"]}],"id":[{"id":"10.13039\/501100004921","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the National Key R&D Program of China","award":["2018YFC2000700"],"award-info":[{"award-number":["2018YFC2000700"]}]},{"name":"the Key Research Program of the Chinese Academy of Sciences","award":["ZDRW-ZS-2017-1"],"award-info":[{"award-number":["ZDRW-ZS-2017-1"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,2,11]]},"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Growth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-\u03baB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      CKI acts on macrophages and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2019-000317","type":"journal-article","created":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T05:20:40Z","timestamp":1584336040000},"page":"e000317","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":149,"title":["Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib"],"prefix":"10.1136","volume":"8","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of 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Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoguang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Beijing Zhendong Pharmaceutical Research Institute Co, Ltd, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingquan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University 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