{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:07:27Z","timestamp":1793369247564,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"unspecified","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["BC200924"],"award-info":[{"award-number":["BC200924"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["BC240454"],"award-info":[{"award-number":["BC240454"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K99CA286969"],"award-info":[{"award-number":["K99CA286969"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R00CA286969"],"award-info":[{"award-number":["R00CA286969"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA260890"],"award-info":[{"award-number":["R01CA260890"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,3,25]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune exclusion inhibits antitumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-na\u00efve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of trophoblast cell-surface antigen 2 (TROP2), a key target of anticancer antibody drug conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-programmed cell death protein 1 (PD-1) therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T-cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T-cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC sacituzumab govitecan, enhances the anti-PD-1 response and improves T-cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD-1 therapy in human breast cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate antitumor immunity and enhance immunotherapy response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012265","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T15:30:18Z","timestamp":1775230218000},"page":"e012265","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["TROP2\/claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1654-198X","authenticated-orcid":false,"given":"Bogang","family":"Wu","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Department of Immunology, Mayo Clinic Arizona, Phoenix, Arizona, 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