{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:38:58Z","timestamp":1792798738603,"version":"4.5.0"},"reference-count":65,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"unspecified","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National High Level Hospital Clinical Research Funding","award":["2022-PUMCH-B-008"],"award-info":[{"award-number":["2022-PUMCH-B-008"]}]},{"name":"Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences","award":["2022-I2M-1-008"],"award-info":[{"award-number":["2022-I2M-1-008"]}],"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,6,16]]},"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neoadjuvant immune checkpoint blockade (nICB) has revolutionized cancer treatment, yet the underlying mechanisms of resistance in bladder cancer remain to be explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells, tumor tissues, adjacent normal tissues, and metastatic lymph nodes from 2 nICB-na\u00efve and 10 nICB-treated patients with bladder cancer (5 responders and 5 non-responders). Spatial RNA sequencing was performed on tumor slides from two responders and four non-responders. Findings were validated by multiplex immunohistochemistry, mice orthotopic bladder cancer model, and flow cytometry assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      nICB remodeled the tumor microenvironment of bladder cancer from both single-cell and spatial perspectives. scRNA-seq analysis revealed a significant increase in MYBL2\n                      <jats:sup>hi<\/jats:sup>\n                      cancer stem cells (CSCs) among non-responders. Analysis of the myeloid population showed that SPP1+ macrophages associated with angiogenesis were linked to CD8+ T\u2009cell exclusion. Further investigation into cell\u2013cell communication revealed a propensity for bidirectional crosstalk between MYBL2\n                      <jats:sup>hi<\/jats:sup>\n                      CSCs and SPP1+ macrophages in non-responders. MYBL2\n                      <jats:sup>hi<\/jats:sup>\n                      CSCs derived CCL15, which bound to CCR1 and induced SPP1 upregulation in macrophages which reciprocally enhanced bladder cancer stemness and resistance to nICB through the SPP1-ITG\u03b19\u03b21 axis. Additionally, we identified an aged CCL3+ neutrophil population that interacted with SPP1+ macrophages through a positive feedback loop, contributing to nICB resistance. Finally, in vivo studies demonstrated that combined MYBL2 knockdown and SPP1 targeting synergistically enhanced ICB efficacy in bladder cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our research reveals transcriptomic characteristics associated with distinct therapeutic responses to nICB treatment, offering a foundation for optimizing personalized neoadjuvant strategies in bladder cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-011319","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T13:30:21Z","timestamp":1752154221000},"page":"e011319","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Malevolent alliance of MYBL2\n                    <sup>hi<\/sup>\n                    cancer stem cell and SPP1+ macrophage confers resistance to neoadjuvant immunotherapy in bladder cancer"],"prefix":"10.1136","volume":"13","author":[{"given":"Hualin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Urology, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"},{"name":"Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"},{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoheng","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 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