{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T23:04:11Z","timestamp":1788563051606,"version":"build-2803163510"},"reference-count":67,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Cancer Moonshot Initiative","award":["ZIA BC 0118542"],"award-info":[{"award-number":["ZIA BC 0118542"]}]},{"DOI":"10.13039\/100031022","name":"Center for Cancer Research","doi-asserted-by":"publisher","award":["ZIA BC 011267"],"award-info":[{"award-number":["ZIA BC 011267"]}],"id":[{"id":"10.13039\/100031022","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031022","name":"Center for Cancer Research","doi-asserted-by":"publisher","award":["ZIA BC 012066"],"award-info":[{"award-number":["ZIA BC 012066"]}],"id":[{"id":"10.13039\/100031022","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Center for Advancing Translational Sciences, Japanese Society for the Promotion of Science","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,19]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited curative treatment options. While chimeric antigen receptor (CAR) T cells have shown some promise in solid tumors, ACC remains largely unexplored in this context. Here, we used patient-derived xenograft (PDX) models of ACC to identify immunotherapeutic targets and develop novel CAR T-cell strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Target identification and tumor microenvironment (TME) profiling were conducted using publicly available bulk and single-cell RNA sequencing data from patients with ACC samples. Surface proteomic analysis and flow cytometry of PDXs were conducted to validate antigen candidates. CAR T cells were engineered and tested for cytotoxicity\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      and profiled using flow cytometry and cytokine analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified ectonucleotide pyrophosphatase\/phosphodiesterase family member 3 (ENPP3) as a shared immunotherapy target in 4\/7 (57%) ACC PDXs. ENPP3-targeted CAR T-cells eradicated &gt;85% of ENPP3\n                      <jats:sup>+<\/jats:sup>\n                      ACC cells\n                      <jats:italic>in vitro<\/jats:italic>\n                      but showed attenuated efficacy in PDX mouse models. Restrained ENPP3 CAR T-cell activity correlated with immunosuppressive features of the TME, particularly the presence of CD206\n                      <jats:sup>+<\/jats:sup>\n                      tumor-associated macrophages (TAMs). Co-treatment with an agent modulating CD206\n                      <jats:sup>+<\/jats:sup>\n                      TAMs restored CAR T-cell function and improved antitumor responses in ENPP3\n                      <jats:sup>high<\/jats:sup>\n                      and ENPP3\n                      <jats:sup>low<\/jats:sup>\n                      PDX models (difference between mean tumor weights \u2212270.1\u2009mg\u00b1117.4; p\n                      <jats:italic>&lt;<\/jats:italic>\n                      0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ENPP3 is a novel target for CAR T-cell therapy in ACC. ENPP3 CAR T cells, when combined with CD206 modulation to overcome immune suppression within the TME, have therapeutic efficacy in ACC by mediating robust tumor growth suppression. This combinatorial strategy, which includes CAR T cells alongside therapies that recalibrate immunosuppressive CD206\n                      <jats:sup>+<\/jats:sup>\n                      TAMs, may be a novel approach for improved immunotherapy of solid cancers beyond ACC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013726","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:11:13Z","timestamp":1782915073000},"page":"e013726","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["ENPP3 CAR T cells combined with CD206 modulation suppress adrenocortical carcinoma"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct03739827","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2584-3026","authenticated-orcid":false,"given":"Reona","family":"Okada","sequence":"first","affiliation":[{"name":"Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnulfo","family":"Mendoza","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl","family":"Nousome","sequence":"additional","affiliation":[{"name":"Advanced Biomedical Computational Science, National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA"},{"name":"Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 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