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The study identifies ATP6V0C, a V-ATPase subunit mediating proton transport, as a key mediator of TME acidification and shows that higher ATP6V0C expression correlates with hepatocellular carcinoma progression and metastasis. To enable real-time monitoring, it introduces a pH-responsive ratiometric photoacoustic sensor (PPS) for dynamic imaging of acidity from early foci to solid tumors. PPS enhances photothermal effects in acidic conditions and, combined with the proton pump inhibitor esomeprazole, synergistically suppresses tumor growth. Overall, PPS-assisted photoacoustic molecular imaging provides a sensitive, specific, noninvasive approach to characterize tumor initiation and progression and supports early diagnostic and therapeutic targeting of acidic TME.",{"@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/multiscale-imaging-on-proton-pump-driven-acidity-for-assessing-tumor-progression-and-metastasis/351085/",{"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/multiscale-imaging-on-proton-pump-driven-acidity-for-assessing-tumor-progression-and-metastasis/351085.png","ImageObject",300,407,{"name":92,"@type":93},"Theodore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is tumor microenvironment acidity important for cancer progression?","Question",{"text":112,"@type":113},"The tumor microenvironment becomes locally acidic and this acidity promotes tumor growth, invasion, and metastasis. It is linked to metabolic reprogramming, proton export, and impaired proton clearance from abnormal tumor vasculature.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What role does ATP6V0C play in tumor acidification?",{"text":117,"@type":113},"ATP6V0C, a V-ATPase subunit responsible for proton transmembrane transport, mediates TME acidification. Higher ATP6V0C expression correlates with hepatocellular carcinoma progression and metastasis.",{"name":119,"@type":110,"acceptedAnswer":120},"How does the developed PPS enable real-time assessment of tumor acidity?",{"text":121,"@type":113},"The pH-responsive ratiometric photoacoustic sensor (PPS) dynamically monitors TME acidity across stages. Using photoacoustic molecular imaging, it visualizes spatiotemporal changes from early tumor foci to solid tumors.","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},351085,1790183451,{"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":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31},7971461740886,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Article [https://doi.org/10.1038/s41467-026-68491-4](https://doi.org/10.1038/s41467-026-68491-4)  \nMultiscale imaging on proton pump-driven acidity for assessing tumor progression and metastasis  \nReceived: 28 February 2025  \n\n| Accepted: 8 January 2026 |\n| --- |\n| |\n| Check for updates |\n\nSilue Zeng1,2,3,4,5,6,10, Jingqin Chen 2,6,10 , Yaguang Ren2,6, Jianyou Gu 7, Junfeng Zhang7, Liangjian Liu2,6, Zhiqiang Xu2,6, Rui Chen8,  \nChuanyu Tang 1,2,3,4,5, Qiang Xue2, Sai Wen1,3,4,5, Haoyu Hu1,3,4,5, Zheng Liu9, Ning Ren9, Chihua Fang 1,3,4,5  & Chengbo Liu 2,6   \nAn acidic tumor microenvironment (TME), a hallmark of cancer progression, promotes tumor growth, invasion, and metastasis. Detecting and targeting tumor acidity have emerged as key frontiers in early cancer diagnosis and treatment. However, current approaches lack sensitive and specific methods to visualize and quantify tumor acidity in vivo across different stages of tumor development. Here we show that ATP6V0C, a subunit of the V-ATPase responsible for proton transmembrane transport, is a critical mediator ofTME acidification. High ATP6V0C expression correlates with hepatocellular carcinoma (HCC) progression and metastasis. To enable real-time assessment of tumor acidity, we develop a pH-responsive ratiometric photoacoustic sensor (PPS) that dynamically monitors TME acidity throughout HCC initiation, progression, and metastasis. Using PPS-assisted photoacoustic molecular imaging, we visualize the spatiotemporal evolution of TME acidity from early tumor foci to solid tumors. PPS exhibits enhanced photothermal effects under acidic conditions, and its combination with the proton pump inhibitor esomeprazole synergistically suppresses tumor growth. Overall, PPS-assisted photoacoustic molecular imaging provides a sensitive and specific approach to characterize tumor initiation and progression, supporting its potential application in early diagnosis and therapeutic strategies that target the acidic TME.  \nThe initiation and progression of cancer are closely associated with alterations in the tumor microenvironment (TME), particularly localized acidification arising from metabolic reprogramming and vascular perfusion abnormalities1. A major contributor to this acidification is enhanced glycolysis in tumor cells, commonly known as the “Warburg effect”, wherein cells preferentially rely on glycolysis for adenosine triphosphate production even under normoxic conditions2, resulting in the accumulation of lactic acid and protons. These acidic metabolites are exported via proton pumps such as V-ATPases and lactate transporters, thereby lowering extracellular pH3,4. In parallel, the  \nstructurally abnormal and poorly perfused tumor vasculator impairs proton (H+) clearance, producing a TME pH typically between 6.5 and 6.85. This acidic milieu is not only a hallmark of cancer progression but also actively promotes tumor growth, invasion, and metastasis4,6, making it an attractive target for diagnostic and therapeutic strategies. However, TME acidity is highly heterogeneous and dynamically evolves in early-stage tumors and metastatic lesions6,7. In these stages, low-level acidification and the complex structure of the extracellular matrix complicate both detection and therapeutic targeting8,9. Thus, there is a pressing need for highly sensitive, specific, and noninvasive  \nA full list of affiliations appears at the end of the paper. [e-mail:](e-mail: jq.chen@siat.ac.cn)[ jq.chen@siat.ac.cn](e-mail: jq.chen@siat.ac.cn); [fangchihua@smu.edu.cn](fangchihua@smu.edu.cn); [cb.liu@siat.ac.cn](cb.liu@siat.ac.cn)  \nimaging tools capable ofdetecting and characterizing TME acidity (i.e., H+ ions), particularly to improve early cancer diagnosis and therapeutic outcomes.  \nBiomedical imaging technologies are indispensable for tumor diagnosis and therapeutic evaluation10–12. Conventional modalities such as magnetic resonance imaging (MRI), ultrasound, and computed tomography are widely used to detect primary ","cbCaiqcrrfur0Nwf","https://ap.wps.com/l/cbCaiqcrrfur0Nwf","pdf",11457012,"English","# Tumor microenvironment acidity and clinical need\n## Limitations of existing imaging approaches\n# Proton pump-driven acidification and molecular target\n# Photoacoustic molecular imaging strategy\n## PPS sensor design for real-time ratiometric monitoring\n# Validation and therapeutic potential","[{\"question\":\"Why is tumor microenvironment acidity important for cancer progression?\",\"answer\":\"The tumor microenvironment becomes locally acidic and this acidity promotes tumor growth, invasion, and metastasis. It is linked to metabolic reprogramming, proton export, and impaired proton clearance from abnormal tumor vasculature.\"},{\"question\":\"What role does ATP6V0C play in tumor acidification?\",\"answer\":\"ATP6V0C, a V-ATPase subunit responsible for proton transmembrane transport, mediates TME acidification. Higher ATP6V0C expression correlates with hepatocellular carcinoma progression and metastasis.\"},{\"question\":\"How does the developed PPS enable real-time assessment of tumor acidity?\",\"answer\":\"The pH-responsive ratiometric photoacoustic sensor (PPS) dynamically monitors TME acidity across stages. Using photoacoustic molecular imaging, it visualizes spatiotemporal changes from early tumor foci to solid tumors.\"}]","Multiscale imaging on proton pump-driven acidity for assessing tumor progression and metastasis | PDF",1790092555]