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We investigated radiotherapy combined with HER2-targeted T cell therapy in an NSCLC model. The antitumor efficacy of radiotherapy and engineered T cells expressing a DAP12-associated synthetic antigen receptor (SAR) targeting HER2 was evaluated in HER2-expressing A549 xenografts. HER2 modulation, transcriptional regulation, and tumor T cell infiltration were assessed using immunoblotting, real-time quantitative polymerase chain reaction, flow cytometry, RNA-seq, and immunohistochemistry. High-dose HER2-SAR T cell infusion abolished A549 tumor growth but induced graft-vs-host disease. Low-dose T cell infusion was well-tolerated and provided partial tumor inhibition. Induction radiotherapy (7 d before T cell infusion) synergistically improved tumor control and survival. Radiotherapy transiently upregulated HER2 expression (4 to 24\u2005h), though administering HER2-SAR T cells within this window did not enhance antitumor efficacy. Radiation did not enhance T cell-mediated cytotoxicity in vitro. However, in tumors, radiotherapy increased intratumoral proliferation and accumulation of HER2-SAR T cells and enhanced the extrinsic apoptotic pathway, including induction of Fas transcript and protein levels and cleaved caspase-3 (CC3). RNA-seq of irradiated tumors revealed lasting transcriptional reprogramming with increased immune activation and decreased proliferation and oncogenic signaling. Induction radiotherapy enhances HER2-SAR T cell infiltration and provides synergistic tumor suppression, likely through additional activation of immune-mediated apoptosis. These findings support further assessment of HER2-SAR T cell therapy in HER2-expressing NSCLC.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag030","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T12:24:52Z","timestamp":1772454292000},"source":"Crossref","is-referenced-by-count":1,"title":["HER2-specific synthetic antigen receptor T cell therapy synergizes with radiotherapy to provide improved antitumor efficacy in non-small cell lung cancer"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-5938","authenticated-orcid":false,"given":"Olga-Demetra","family":"Biziotis","sequence":"first","affiliation":[{"name":"Centre for Metabolism, Obesity and Diabetes Research, McMaster University , 1280 Main St W, Hamilton, Ontario , L8S 4K1","place":["Canada"]},{"name":"Centre for Discovery in Cancer Research, McMaster University , 1280 Main St W, Hamilton, Ontario , L8S 4M1","place":["Canada"]},{"name":"Department of Oncology, McMaster University , 699 Concession St, Hamilton, Ontario , L8V 5C2","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Centre for Discovery in Cancer Research, McMaster University , 1280 Main St W, Hamilton, Ontario , L8S 4M1","place":["Canada"]},{"name":"McMaster Immunology Research Centre, McMaster University , 1280 Main St W, Hamilton, Ontario , L8S 4K1","place":["Canada"]},{"name":"Department of Medicine, McMaster University , 1200 Main St W, Hamilton, Ontario , L8N 3Z5","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7406-7154","authenticated-orcid":false,"given":"Allyson E","family":"Moore","sequence":"additional","affiliation":[{"name":"Centre for Discovery in Cancer Research, McMaster University , 1280 Main St W, Hamilton, Ontario , L8S 4M1","place":["Canada"]},{"name":"McMaster Immunology 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