{"doi":"10.1158/2159-8290.cd-23-0434","title":"EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth","abstract":"The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth. SIGNIFICANCE: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.","journal":"Cancer Discovery","year":2024,"id":420352,"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":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":233744,"name":"Thekla Cordes","orcid":"0000-0002-8097-191X","position":1,"is_corresponding":false},{"id":615025,"name":"Ziyan Xu","orcid":"0000-0003-1270-135X","position":2,"is_corresponding":false},{"id":891565,"name":"Ramya S. Kuna","orcid":"0000-0002-8104-4720","position":3,"is_corresponding":false},{"id":996454,"name":"Kacie A. Traina","orcid":"0000-0002-7799-3253","position":4,"is_corresponding":false},{"id":973804,"name":"Camila Robles-Oteíza","orcid":"0000-0001-7157-9572","position":5,"is_corresponding":false},{"id":345036,"name":"Deborah Ayeni","orcid":"0000-0002-1350-9303","position":6,"is_corresponding":false},{"id":106540,"name":"Elizabeth M. Kwong","orcid":null,"position":7,"is_corresponding":false},{"id":566891,"name":"Stellar Levy","orcid":"0009-0006-0731-4274","position":8,"is_corresponding":false},{"id":1014133,"name":"Anna-Maria Globig","orcid":"0000-0002-5236-7459","position":9,"is_corresponding":false},{"id":1211257,"name":"Matthew M. Nobari","orcid":"0000-0002-6743-7683","position":10,"is_corresponding":false},{"id":789669,"name":"George Z. Cheng","orcid":"0000-0001-6859-8705","position":11,"is_corresponding":false},{"id":106558,"name":"Sandra L. Leibel","orcid":"0000-0001-6867-2477","position":12,"is_corresponding":false},{"id":41685,"name":"Robert Homer","orcid":"0000-0002-2055-5885","position":13,"is_corresponding":false},{"id":407740,"name":"Reuben J. Shaw","orcid":"0000-0002-1555-8977","position":14,"is_corresponding":false},{"id":229039,"name":"Christian M. Metallo","orcid":"0000-0003-2404-3040","position":15,"is_corresponding":false},{"id":1261,"name":"Katerina Politi","orcid":"0000-0001-6064-4527","position":16,"is_corresponding":false},{"id":84672,"name":"Susan M. Kaech","orcid":"0000-0003-1674-1420","position":17,"is_corresponding":false},{"id":1185428,"name":"Alexandra Kuhlmann-Hogan","orcid":"0009-0003-0208-8907","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T01:57:25.777459Z","pmid":"38241033","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":[]}