ArticleCancer immunology research2022
Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma.
Article in Cancer immunology research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 115 citations in OpenAlex.
- Time matters: circadian genetics and the molecular logic of human health and disease.Nature reviews. Genetics · 2026Review
- Review
- Modulation of the tumor microenvironment through BMAL1-LHX8 axis augments the sensitivity of ameloblastoma to vemurafenib.Journal of advanced research · 2026Article
- Galanin impairs tumor immunity in glioblastoma by promoting infiltration and ferroptosis resistance of myeloid-derived suppressor cells.Nature cancer · 2026Article
- Immunotherapy for Glioma: A compartmental framework for resistance and rational combination design.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- The circadian architecture of tumor immunity: mechanistic insights and treatment strategies.Biomarker research · 2026Review
- Olfml3 Regulates Microglial Inflammation and Neuronal Injury in Obstructive Sleep Apnea via Cybb-Mediated TLR4/NF-κB Pathway.CNS neuroscience & therapeutics · 2026Article
- Integrative multi-omics analysis and machine learning identify M2 macrophage-induced ferroptosis resistance in glioblastoma.Functional & integrative genomics · 2026Article
- Circadian gene CLOCK-mediated LLPS of NBR1 and p62/SQSTM1 inhibits proliferation and migration of nasopharyngeal carcinoma.Cell death & disease · 2026Article
- Symbiotic exclusivity between CLOCK and TFPI2 drives stemness and immunosuppression in glioblastoma models.The Journal of clinical investigation · 2026Article
- Uncovering a feedback loop in glioblastoma that reinforces stemness and immunosuppression.The Journal of clinical investigation · 2026Article
- The biological clock in parkinson's disease: mechanisms and chronotherapy.NPJ Parkinson's disease · 2026Review
- Circadian-driven transcriptional programs govern metastatic progression.Cancer biology & medicine · 2026Review
- M2-like GAMs secreting CSTA drive glioblastoma progression via the ITGB4-TGFB1 feedback axis.Journal of translational medicine · 2026Article
- Nutritional modulation of metabolic signaling within the tumor microenvironment for cancer therapy.Molecular and cellular biochemistry · 2026Review
- The Potential of Chronotherapy and Nanotherapy-Based Strategies for Glioblastoma Treatment.Pharmaceutics · 2026Review
- Temporal dynamics in cancer immunotherapy: the interplay between circadian rhythms, tumor microenvironment, and immune checkpoint blockade.Journal of the National Cancer Center · 2026Review
- Article
- Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels.The Journal of clinical investigation · 2026Article
- Circadian clock and cancer.Military Medical Research · 2026Review
29 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSC) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK-BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162 and polarizes infiltrating microglia toward an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK-OLFML3-HIF1α-LGMN-CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8+ T-cell infiltration, activation, and cytotoxicity, and synergizes with anti-programmed cell death protein 1 (anti-PD-1 therapy). In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial abundance and poor prognosis. Together, these findings uncover the CLOCK-OLFML3-HIF1α-LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for patients with GBM.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.