{"doi":"10.1084/jem.20242282","title":"Tumor cell heterogeneity drives spatial organization of the intratumoral immune response","abstract":"Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of \"hot\" and \"cold\" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a \"dominant cold\" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.","journal":"The Journal of Experimental Medicine","year":2025,"id":510780,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":571591,"name":"Lotus Lum","orcid":"0000-0003-4751-0764","position":1,"is_corresponding":false},{"id":553724,"name":"Kenneth H. Hu","orcid":"0000-0002-0294-0202","position":2,"is_corresponding":false},{"id":1367533,"name":"Piyush Chaudhary","orcid":null,"position":3,"is_corresponding":false},{"id":1367896,"name":"Savannah Hughes","orcid":"0009-0007-3593-6756","position":4,"is_corresponding":false},{"id":1368508,"name":"Cecilia Ledezma-Soto","orcid":null,"position":5,"is_corresponding":false},{"id":620243,"name":"Bushra Samad","orcid":"0000-0002-2893-0897","position":6,"is_corresponding":false},{"id":34048,"name":"Daphne Superville","orcid":"0000-0002-8317-8431","position":7,"is_corresponding":false},{"id":425728,"name":"Kenneth Ng","orcid":"0009-0003-7733-2636","position":8,"is_corresponding":false},{"id":476733,"name":"Arun K. Chumber","orcid":"0009-0004-8247-437X","position":9,"is_corresponding":false},{"id":1367897,"name":"Ciara Benson","orcid":"0000-0002-6258-7412","position":10,"is_corresponding":false},{"id":1367898,"name":"Zoe N. Adams","orcid":"0009-0004-5331-5804","position":11,"is_corresponding":false},{"id":811556,"name":"Kelly Kersten","orcid":"0000-0001-7615-2594","position":12,"is_corresponding":false},{"id":297322,"name":"Oscar A. Aguilar","orcid":"0000-0002-7990-8745","position":13,"is_corresponding":false},{"id":24099,"name":"Lawrence Fong","orcid":"0000-0002-6428-428X","position":14,"is_corresponding":false},{"id":553722,"name":"Alexis J. Combes","orcid":"0000-0002-9110-6542","position":15,"is_corresponding":false},{"id":240181,"name":"Matthew F. Krummel","orcid":"0000-0001-7915-3533","position":16,"is_corresponding":false},{"id":727673,"name":"Melissa Quino Reeves","orcid":"0000-0002-4886-5164","position":17,"is_corresponding":false},{"id":1367895,"name":"Miho Tanaka","orcid":"0000-0002-0905-9346","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:47:50.575618Z","pmid":"40167599","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":[]}