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Metabolic alterations, particularly extracellular acidification, critically impair drug response yet remain underexplored in clinical stratification. We present a sensing\u2010integrated 3D platform that enables non\u2010invasive time\u2010resolved mapping of pH dynamics in patient\u2010derived tumorspheres. Primary PDAC cells from five patients were embedded in an alginate\u2010based matrix incorporating ratiometric optical pH sensors, allowing real\u2010time monitoring of local extracellular acidification associated with individual cells during treatment. In contrast to existing bulk or invasive methods, our platform captures extracellular acidification dynamics with high spatial and temporal resolution in a 3D model with potential clinical relevance. Distinct extracellular acidification profiles emerged in response to FOLFIRINOX, gemcitabine, and paclitaxel. These metabolic signatures correlated with treatment efficacy and highlighted patient\u2010specific drug sensitivities. This platform offers a rapid, scalable tool for personalized drug screening and highlights a potential role of pH metabolic heterogeneity in PDAC chemoresistance. It may complement existing clinical workflows by providing early predictive insights into patient\u2010specific therapeutic outcomes.<\/jats:p>","DOI":"10.1002\/smll.75149","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:58:36Z","timestamp":1786615116000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sensing\u2010Integrated Patient\u2010Derived Tumorspheres Predict Chemotherapeutic Efficacy via Local Extracellular pH Dynamics"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6719-1591","authenticated-orcid":false,"given":"Stefania","family":"Forciniti","sequence":"first","affiliation":[{"name":"Institute of Nanotechnology National Research Council (CNR\u2010NANOTEC) c\/o Campus Ecotekne  Lecce Italy"},{"name":"Tecnomed Puglia \u2013 Technopole for Precision Medicine (Biotech Lecce Hub) c\/o Campus Ecotekne Lecce 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