{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:15:28Z","timestamp":1792066528956,"version":"4.4.0"},"reference-count":53,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"unspecified","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2023A1515010217"],"award-info":[{"award-number":["2023A1515010217"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2024A1515010620"],"award-info":[{"award-number":["2024A1515010620"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Undergraduate Training Program for Innovation and Entrepreneurship","award":["202412121007"],"award-info":[{"award-number":["202412121007"]}]},{"name":"National Undergraduate Training Program for Innovation and Entrepreneurship","award":["202412121038"],"award-info":[{"award-number":["202412121038"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573090"],"award-info":[{"award-number":["82573090"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,22]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The acidic tumor microenvironment (TME) is a major driver of immunosuppression and tumor progression in breast cancer. Although myosin VI (MYO6), an actin-dependent motor protein, is frequently upregulated in malignancies, its function in immune remodeling remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To identify MYO6 as a regulator of acidic TME remodeling and macrophage polarization in breast cancer, elucidate the underlying mechanism, and evaluate its therapeutic relevance for anti-programmed death-ligand 1 (anti-PD-L1) therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Integrated analyses of The Cancer Genome Atlas and Gene Expression Omnibus datasets were performed to evaluate the association of MYO6 with prognosis and M2 tumor-associated macrophage (TAM) infiltration in breast cancer. Transcriptomic, molecular, cellular, and pharmacological approaches were used to investigate MYO6-mediated acidic TME remodeling and macrophage polarization. In vivo studies assessed the effects of MYO6 inhibition by 2,4,6-triiodophenol (TIP) on tumor acidification, immunity, and anti-PD-L1 efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MYO6 expression correlated with M2 TAM infiltration and poor prognosis in breast cancer. Mechanistically, nuclear MYO6 recruited SP1 and RNA polymerase II to the carbonic anhydrase 9 (CA9) promoter, upregulating CA9 and promoting acidification. The acidic TME activated the proton-sensing receptor GPR65 and the cAMP\/PKA\/CREB pathway in macrophages, driving M2 polarization. TIP-mediated MYO6 inhibition reduced acidification, restored antitumor immunity, and enhanced anti-PD-L1 efficacy in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MYO6 is a key molecule regulating breast cancer immune suppression and immunotherapy responsiveness. By promoting CA9-dependent extracellular acidification, MYO6 drives macrophage M2 polarization through the GPR65\/cAMP\/PKA\/CREB pathway. Targeting MYO6 with TIP may represent a promising strategy to overcome resistance to anti-PD-L1 therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015423","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:40:15Z","timestamp":1785411615000},"page":"e015423","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Myosin VI drives breast cancer progression via SP1\/CA9-mediated acidic tumor microenvironment remodeling and subsequent M2 macrophage polarization"],"prefix":"10.1136","volume":"14","author":[{"given":"Fang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of 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