{"doi":"10.1101/2023.03.02.530835","title":"<i>Zbtb46</i> coordinates angiogenesis and immunity to control tumor outcome","abstract":"Abstract Tumor-angiogenesis and -immunity play critical roles in cancer progression and outcome. An inverse correlation of these two 1 hints at common regulatory mechanism(s). Here, we report that Zbtb46 , a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs) 2, 3 , constitutes one such regulatory mechanism. Zbtb46 was downregulated in both DCs and endothelial cells (ECs) by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive cell accumulation. Analysis of cancer patient data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression mitigated the pro-tumor TME features and restricted tumor growth. Mechanistically, Zbtb46- deficient ECs were highly angiogenic, and Zbtb46- deficient bone-marrow progenitors upregulated Cebpb and diverted the DC program to myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer 4–7 . Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb , skewed bone-marrow precursors towards more DC generation over macrophages, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in pre-clinical models. These findings identify Zbtb46 as a common regulatory mechanism for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":403548,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":644803,"name":"Madhav Subramanian","orcid":"0000-0002-1957-4982","position":1,"is_corresponding":false},{"id":366985,"name":"Jun Wu","orcid":"0000-0002-1891-368X","position":2,"is_corresponding":false},{"id":1004965,"name":"Minseo Kim","orcid":"0000-0003-0253-0921","position":3,"is_corresponding":false},{"id":366984,"name":"Karen Krchma","orcid":"0000-0003-0800-8456","position":4,"is_corresponding":false},{"id":607030,"name":"Xiaoli Wang","orcid":"0000-0003-3136-9807","position":5,"is_corresponding":false},{"id":395921,"name":"Carmen M. Halabi","orcid":"0000-0003-4889-8131","position":6,"is_corresponding":false},{"id":275337,"name":"Hua Pan","orcid":"0009-0001-1526-7205","position":7,"is_corresponding":false},{"id":372176,"name":"Samuel A. Wickline","orcid":"0000-0002-8949-3192","position":8,"is_corresponding":false},{"id":225534,"name":"Daved H. Fremont","orcid":"0000-0002-8544-2689","position":9,"is_corresponding":false},{"id":297330,"name":"Kyunghee Choi","orcid":"0000-0002-9634-9375","position":10,"is_corresponding":false},{"id":644802,"name":"Ashraf Ul Kabir","orcid":"0000-0002-9449-8238","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T01:20:36.280647Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}