02592nas a2200577   4500000000100000000000100001008004100002260001500043653002700058653002500085653001800110653001800128653002300146100001600169700002600185700001600211700001700227700001700244700002100261700001300282700001700295700001400312700001800326700002300344700002200367700001500389700001400404700001400418700001300432700001800445700001800463700001300481700001400494700001500508700002100523700001700544700002100561700001200582700001600594700001700610700002500627700001900652700001900671700002200690700002000712245008500732856005500817300000900872520111900881022001402000       2025                            d  c2025-10-1710aBiomedical Engineering10acancer immunotherapy10aCancer models10aLab-on-a-chip10aTissue engineering1 aHaijiao Liu1 aEstela Noguera-Ortega1 aXuanqi Dong1 aWon Dong Lee1 aJeehan Chang1 aSezin Aday Aydin1 aYumei Li1 aYonghee Shin1 aXinyi Shi1 aMaria Liousia1 aMarina C. Martinez1 aJoshua J. Brotman1 aSoyeon Kim1 aZeyu Chen1 aAnni Wang1 aZirui Ou1 aJungwook Paek1 aJu Young Park1 aAidi Liu1 aHaonan Hu1 aZebin Xiao1 aDora Maria Racca1 aSe-jeong Kim1 aG. Scott Worthen1 aWei Guo1 aEllen Puré1 aTaewook Kang1 aJoshua D. Rabinowitz1 aE. John Wherry1 aEdmund K. Moon1 aSteven M. Albelda1 aDan Dongeun Huh00aA tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors  uhttps://www.nature.com/articles/s41587-025-02845-z  a1-173 aOur limited understanding of cancer–immune interactions remains a critical barrier to advancing chimeric antigen receptor (CAR)-T cell therapy for solid malignancies. Here, we present a microengineered system that enables vascularization of human tumor explants and their controlled perfusion with immune cells to model the activity of CAR-T cells in the tumor microenvironment. Using vascularized human lung adenocarcinoma tumors, we first demonstrate the ability of our tumor-on-a-chip system to simulate, visualize and interrogate CAR-T cell function. We then test a chemokine-directed CAR-T cell engineering strategy in a model of malignant pleural mesothelioma and validate our findings in a matching in vivo mouse model. Finally, we describe a potential therapeutic target that can be pharmacologically modulated to increase the efficacy of CAR-T cells in lung adenocarcinoma, for which we present biomarkers identified by global metabolomics analysis. Our microphysiological system provides promising in vitro technology to advance the development of adoptive cell therapies for cancer and other diseases.  a1546-1696