{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:24:05Z","timestamp":1790619845518,"version":"4.1.0"},"reference-count":65,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":59,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R01 NS124594,R01NS127824"],"award-info":[{"award-number":["R01 NS124594,R01NS127824"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DoD","award":["W81XWH-21-1-0380"],"award-info":[{"award-number":["W81XWH-21-1-0380"]}]},{"name":"Cancer Research Institute","award":["CLIP Grant CRI13662"],"award-info":[{"award-number":["CLIP Grant CRI13662"]}]},{"name":"VeloSano","award":["VeloSano Award"],"award-info":[{"award-number":["VeloSano Award"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,15]]},"abstract":"<jats:p>Glioblastoma (GBM) is a highly aggressive brain tumor characterized by extensive crosstalk between glioblastoma stem cells (GSCs) and immunosuppressive microglia, with our previous work identifying CLOCK and TFPI2 as key regulators of this interaction. Here, we uncover a \u2018symbiotic exclusivity\u2019 pattern between CLOCK and TFPI2, showing that, despite mutually exclusive amplifications, they sustain symbiotic regulatory interactions in GBM. The CLOCK-BMAL1 complex transcriptionally upregulates TFPI2, while TFPI2-driven hypoxia inducible factor 1 \u03b1 (HIF-1\u03b1) signaling activates nuclear factor k B (NF-kB) P65 to upregulate the CLOCK-BMAL1 complex, creating a positive feedback loop to promote stemness, immunosuppression, and tumor progression. Disrupting the CLOCK-TFPI2 interplay through dual inhibition of their downstream effectors reduces GSC stemness and immunosuppressive microglia, activates antitumor immunity, and synergizes with anti-PD1 therapy to achieve complete tumor regression in 50%\u201362.5% of tumor-bearing mice. This study uncovers a promising therapeutic strategy for a broader subset of patients with GBM with high expression of either CLOCK or TFPI2, and provides a framework for identifying \u2018symbiotic exclusivity\u2019 genes in cancer.<\/jats:p>\n                  <jats:p>Scientists discovered two genes that cooperate to help aggressive brain tumors grow and evade immunity. Targeting both pathways boosts immune therapy and shrinks tumors in mice.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1172\/jci199056","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T16:00:13Z","timestamp":1773763213000},"source":"Crossref","is-referenced-by-count":3,"title":["Symbiotic exclusivity between CLOCK and TFPI2 drives stemness and immunosuppression in glioblastoma models"],"prefix":"10.1172","volume":"136","author":[{"given":"Fei","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Cancer Sciences, Cleveland Clinic, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhi","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Cancer Sciences, Cleveland Clinic, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cancer Sciences, 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