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To address these limitations, we develop a novel multi\u2010targeting \u201cBicephali\u201d CAR\u2010T platform featuring a dual\u2010transmembrane protein with two distinct extracellular antigen\u2010binding domains and a shared intracellular 4\u20101BB co\u2010stimulatory\/CD3\u03b6 signaling domain. CD276 and NKG2D ligands (NKG2DLs) show high and heterogeneous expression in non\u2010small cell lung cancer (NSCLC) and are undetectable in normal tissues. Bicephali CAR\u2010T cells targeting CD276 and NKG2DLs demonstrate superior tumoricidal activity against NSCLC than conventional BB002 CAR\u2010T cells in vitro and in vivo, together with improved immunological synapse formation and mitochondrial metabolic fitness. In homogeneous NSCLC models co\u2010expressing CD276 and NKG2DLs, Bicephali CAR\u2010T cells achieve prolonged survival outcomes compared to monospecific CAR\u2010T cells. In antigenically heterogeneous NSCLC, Bicephali CAR\u2010T cells more consistently control tumors and prolong survival, whereas monospecific CAR\u2010T cells fail to eliminate tumors following antigen loss. Mechanistically, improved mitochondrial fitness and antioxidant capacity in Bicephali CAR\u2010T cells are associated with sustained T cell function, preserved stem\u2010like differentiation, and durable effector responses. These findings support a multi\u2010targeting CAR\u2010T approach to address antigen heterogeneity in NSCLC and potentially other solid tumors.<\/jats:p>","DOI":"10.1002\/advs.77992","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Multi\u2010Targeting Chimeric Antigen Receptor\u2010T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non\u2010Small Cell Lung Cancer"],"prefix":"10.1002","author":[{"given":"Lina","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Shanghai Key Laboratory of Tissue Engineering Shanghai Ninth People's Hospital Shanghai Jiaotong University School of Medicine  Shanghai China"},{"name":"Institute of Respiratory Diseases Shanghai Jiao Tong University School of Medicine  Shanghai 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