{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:09:56Z","timestamp":1789729796486,"version":"4.0.1"},"reference-count":41,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"unspecified","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Enzo & Me PCF","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"MD Anderson Odyssey Fellowship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,9,22]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using an experimental syngeneic OS lung metastasis BALB\/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate \u03b2-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with \u03b2-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the pretreatment settings, mice treated with \u03b2-glucan prior to OS cell infusion developed significantly fewer lung tumor burdens and had increased survival. Pretreatment with \u03b2-glucan prevented tumor cell seeding in the lungs. In tumor-bearing mice, \u03b2-glucan treatment significantly suppressed tumor growth and prolonged overall survival. \u03b2-glucan treatment increased activated pro-inflammatory M1-like macrophages and natural killer (NK) cells secreting interferon-\u03b3 and granzyme B in the lungs. Depletion studies showed that the antitumor effect of \u03b2-glucan was dependent on macrophages and NK cells. Additionally, \u03b2-glucan treatment also induced myelopoiesis in the bone marrow. The therapeutic benefit of \u03b2-glucan was further augmented when combined with CD40a. Combination therapy significantly increased the infiltration of activated macrophages, including tumor necrosis factor-\u03b1 secreting macrophages, and NK cells into the lungs compared with monotherapy. Bulk RNA sequencing of lung tissue revealed that the combination treatment group exhibited enhanced activation of antitumor innate immune pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, our findings demonstrate the antitumor activity of \u03b2-glucan against OS lung tumor burden, that combining \u03b2-glucan and CD40a increases therapeutic activity, and that this activity is mediated by activation of innate immunity (macrophages and NK cells).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012510","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T10:50:23Z","timestamp":1760352623000},"page":"e012510","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of osteosarcoma lung metastases by \u03b2-glucan and CD40 agonist is mediated by activation of macrophages and NK cells"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3418-6790","authenticated-orcid":false,"given":"Pradeep","family":"Shrestha","sequence":"first","affiliation":[{"name":"Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rejeena","family":"Shrestha","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"},{"name":"Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenie S","family":"Kleinerman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"},{"name":"Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"2025111301352210000_13.10.e012510.1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41572-022-00409-y","article-title":"Osteosarcoma","volume":"8","author":"Beird","year":"2022","journal-title":"Nat Rev Dis Primers"},{"key":"2025111301352210000_13.10.e012510.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMRA2103423\/SUPPL_FILE\/NEJMRA2103423_DISCLOSURES.PDF"},{"key":"2025111301352210000_13.10.e012510.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14646-w"},{"key":"2025111301352210000_13.10.e012510.4","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2020.00013","article-title":"Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression","volume":"10","author":"Fan","year":"2020","journal-title":"Front Oncol"},{"key":"2025111301352210000_13.10.e012510.5","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-001772","article-title":"Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes","volume":"9","author":"Ligon","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2025111301352210000_13.10.e012510.6","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2047"},{"key":"2025111301352210000_13.10.e012510.7","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21155207","article-title":"Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy","volume":"21","author":"Cersosimo","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2025111301352210000_13.10.e012510.8","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.canlet.2018.10.011","article-title":"Tumor-associated macrophages promote lung metastasis and induce epithelial-mesenchymal transition in osteosarcoma by activating the COX-2\/STAT3 axis","volume":"440\u2013441","author":"Han","year":"2019","journal-title":"Cancer Lett"},{"key":"2025111301352210000_13.10.e012510.9","doi-asserted-by":"publisher","DOI":"10.1097\/00000421-199504000-00001"},{"key":"2025111301352210000_13.10.e012510.10","doi-asserted-by":"publisher","DOI":"10.1007\/BF01741788"},{"key":"2025111301352210000_13.10.e012510.11","doi-asserted-by":"crossref","unstructured":"Meyers PA , Chou AJ . 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