{"doi":"10.1101/2025.11.21.689807","title":"TAp73 mediates anti-tumor immunity through regulation of lipid metabolism in the lung tumor microenvironment","abstract":"ABSTRACT While immunotherapy has become the standard of care for lung adenocarcinoma (LUAD) patients without actionable genomic alterations, only a subset of patients benefits from a long-lasting response to immunotherapy. Activation of p53-related signals has emerged as a potential mediator of the lung tumor microenvironment (TME). Given that mutant-p53 interacts with p73 extensively and TAp73-deficient mice develop LUAD, we engineered a mouse model with conditional deletion of TAp73 to understand the interactions of the p53 family in the TME and in metabolic pathways that impact anti-tumor immunity. We demonstrated that TAp73 exerts a tumor-suppressive role in Kras G12D -driven LUAD by regulating lipid metabolism in the TME. We identified a TAp73-driven transcriptional signature involving genes in the arachidonic acid metabolism pathway operational in tumor-associated macrophages that favors T-cell activation and thus anti-tumor immunity. Similar transcriptional changes are seen in macrophages from LUAD patients with p53 mutations and in association with response to immunotherapy. SIGNIFICANCE There is a need to understand how the LUAD TME impacts patient response to immunotherapy. We identified a transcriptional program enacted by TAp73 in tumor alveolar macrophages that supports T-cell activation. Transcriptional and metabolomic data from LUAD patients supports the relevance of this program in response to immune checkpoint inhibition.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559580,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"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":680048,"name":"Vanessa Rubio","orcid":"0000-0003-1214-4397","position":1,"is_corresponding":false},{"id":776162,"name":"Andrew John Davis","orcid":"0000-0002-8839-6542","position":2,"is_corresponding":false},{"id":346966,"name":"John H. 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