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Differential gene analysis of tumor-infiltrating versus non-tumor NK cells from advanced prostate cancer and patient flow cytometry across mouse cancer models show autophagic pathway deregulation. Cancer exposure reduces mitochondrial polarization and effector functions via a CCAAT enhancer binding protein beta (C/EBPβ) program downstream of CXCL12–CXCR4, where CXCR4 and C/EBPβ inhibition restores NK fitness. Autophagy activation strengthens NK and CAR-NK cytotoxicity for tumor control.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/cebp-dependent-autophagy-inhibition-hinders-nk-cell-function-in-cancer/332813/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/cebp-dependent-autophagy-inhibition-hinders-nk-cell-function-in-cancer/332813.png","ImageObject",300,407,{"name":92,"@type":93},"Seraphina","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study address in cancer immunotherapy?","Question",{"text":112,"@type":113},"Most cancers impair NK cell functionality, reducing the effectiveness of cell-based therapies in solid tumors.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What does the study identify as central to NK anti-tumor function?",{"text":117,"@type":113},"Autophagy is identified as a central intracellular regulator of NK cell anti-tumor activity.",{"name":119,"@type":110,"acceptedAnswer":120},"How is C/EBPβ connected to NK cell regulation in the tumor context?",{"text":121,"@type":113},"CCAAT enhancer binding protein beta (C/EBPβ), downstream of the CXCL12–CXCR4 interaction, regulates NK cell metabolism and functional performance.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},332813,1790133061,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},962075114101,"https://ap-avatar.wpscdn.com/avatar/e000253a75eb197efd?x-image-process=image/resize,m_fixed,w_180,h_180&k=1780044092746381165","Article [https://doi.org/10.1038/s41467-024-54355-2](https://doi.org/10.1038/s41467-024-54355-2)  \nC/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer  \nReceived: 18 December 2023  \n\n| Accepted: 5 November 2024 |\n| --- |\n| |\n| Check for updates |\n\nFederica Portale1, Roberta Carriero 2, Marta Iovino1, Paolo Kunderfranco 2  \n,  \nMarta Pandini1,3, Giulia Marelli1, Nicolò Morina1,3, Massimo Lazzeri 4, Paolo Casale4, Piergiuseppe Colombo5, Gabriele De Simone6, Chiara Camisaschi6, Enrico Lugli 6, Gianluca Basso7, Javier Cibella7, Sergio Marchini7, Matteo Bordi 8, Greta Meregalli1, Anna Garbin1,  \nMonica Dambra9, Elena Magrini 9, Wiebke Rackwitz10,11, Francesco Cecconi8,12, Alessandro Corbelli13, Fabio Fiordaliso 13, JiriEitler10,11,14, Torsten Tonn 10,11,14 & Diletta Di Mitri1,3   \nNK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagyas an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies.  \nImmunotherapies represent a groundbreaking discovery in the field of cancer and hold promise for revolutionizing tumor treatment. Among them, T-cell transfer therapies have been applied to treat abroad range of tumors with promising results1. However, the efficacyofT cell-based approaches relies on tumor antigen presentation and expression of major histocompatibility complex (MHC) molecules and it is affected by the engagement of checkpoints that hamper T  \ncell activation. As a consequence, T cell-based immunotherapies showed limited clinical benefits, and innate cells, including natural killer (NK) cells, are now under investigation as candidates for novel strategies that harness innate immunity2–6. NK cells are specialized immune effector cells endowed with the ability to spontaneously identify and kill stressed, foreign, infected, and transformed cells7,8. NK cells are featured by a robust cytotoxic activity, based on the  \nA full list of affiliations appears at the end of the paper. e-mail: diletta.di_mitri@humanitasresearch. it  \nrelease of cytolytic granules and cytotoxic cytokines as well as on the antibody-dependent cellular cytotoxicity (ADCC) mechanism9,10. In addition, NK cells shape the anti-tumor adaptive immune response and engage with lymphoid and dendritic subsets in the tumormicroenvironment (TME)5,11. NK cell-mediated killing is independent from human leukocyte antigen (HLA)-restriction and it is orchestrated by a repertoire of activating and inhibitory receptors that recognize germline-encoded ligands expressed by transformed cells. Importantly, the absence of class I MHC molecules, often downregulated in cancer cells, hampers T-cell recognition but triggers NK elimination of tumor cells. As a consequence, NK cells may ove","cbCaikMBZwpbytC1","https://ap.wps.com/l/cbCaikMBZwpbytC1","pdf",3237457,21,"English","# Background\n## Limitations of T cell-based immunotherapies and NK cell role\n## NK cell activation, cytotoxicity, and tumor microenvironment\n# Autophagy as a regulator of NK function\n## Autophagy overview and “Goldilocks Zone” concept\n## Autophagic pathway deregulation in tumor-infiltrating NK cells\n# Mechanistic pathway and therapeutic implications\n## C/EBPβ downstream of CXCL12–CXCR4 in NK metabolism\n## CXCR4/C/EBPβ inhibition and autophagy activation to restore function","[{\"question\":\"What problem does the study address in cancer immunotherapy?\",\"answer\":\"Most cancers impair NK cell functionality, reducing the effectiveness of cell-based therapies in solid tumors.\"},{\"question\":\"What does the study identify as central to NK anti-tumor function?\",\"answer\":\"Autophagy is identified as a central intracellular regulator of NK cell anti-tumor activity.\"},{\"question\":\"How is C/EBPβ connected to NK cell regulation in the tumor context?\",\"answer\":\"CCAAT enhancer binding protein beta (C/EBPβ), downstream of the CXCL12–CXCR4 interaction, regulates NK cell metabolism and functional performance.\"}]","C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer | PDF",1789999586,53]