S2527
Radiobiology – Immuno-radiobiology
ESTRO 2026
Radiation Physics, Heidelberg, Germany. 5 Helmholtz- Zentrum Dresden-Rossendorf, Dresden, Institute of Radiooncology-OncoRay, Dresden, Germany. 6 INSERM U1086 ANTICIPE, Comprehensive Cancer Center François Baclesse, Caen, France. 7 US PLATON, ORGAPRED Core Facility, University of Caen Normandie, Caen, France. 8 Department of Head and Neck Surgery, Caen University Hospital, Caen, France. 9 Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiotherapy and Radiation Oncology, Institute of Radiooncology - OncoRay, Dresden, Germany. 10 Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. 11 Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Mildred Scheel Early Career Center, Dresden, Germany. 12 Helmholtz- Zentrum Dresden-Rossendorf, Institute of Radiooncology – OncoRay, Dresden, Germany Purpose/Objective: Locally advanced head and neck squamous cell carcinoma (HNSCC) often has poor outcomes due to frequent locoregional and distant recurrences, driven by the biological heterogeneity of the disease. Human papillomavirus (HPV) status is a favorable prognostic factor, whereas HPV-negative HNSCC has a weak antitumor immune response and is classified as “immune cold”. Proton radiotherapy (RT) has been reported to enhance the anti-tumor immune response by increasing clustered DNA lesions and elevating cytokine release(1,2). Thus, reliable predictive biomarkersand more personalized treatment options for high-risk HPV-negative patients are urgently warranted. We previously found that CD98-related amino acid transporters (AATs) are clinically relevant prognostic markers of locoregional control and regulators of radiosensitivity in HPV-negative HNSCC(3,4,5,6). In this study, we analyze the potential immunostimulatory effect of photon versus proton RT when combined with next-generation CAR therapy to treat HPV-negative HNSCC. Material/Methods: The CD98hc-associated AAT–mediated radioresistance in HNSCC (Cal33, FaDu) was investigated by analyzing DNA damage signaling and redox homeostasis using molecular and radiobiological assays, including Western blotting, qPCR, ROS and γ H2AX analyses and scRNA-seq. The antitumor potential of X-ray and proton irradiation combined with UniCAR-based immunotherapy is evaluated in 3D HNSCC spheroids (FaDu Parental-mCherry, Cal33 RR-mCherry) and patient-derived tumor organoids (PDTOs). The switchable UniCAR system, activated via short-lived target modules (TMs), enables control of T-cell cytotoxicity. Standard immunological assays and flow
infiltrating lymphocytes (TILs) were quantified by flow cytometry; mitochondrial mass and membrane potential were measured using MitoTracker dyes; and metabolic reliance was profiled by SCENITH. The functional role of fatty-acid oxidation (FAO) was tested through in vivo blockade of carnitine palmitoyltransferase 1a (CPT1a) with etomoxir. Results: Fractionated RT elicited stronger type I interferon responses and superior tumor control compared to single-dose RT, in a STING-dependent manner. Ablation of STING abolished the survival benefit of fractionated RT. CD8 ⁺ TILs after RT exhibited increased mitochondrial membrane potential without altered mitochondrial mass, indicating improved mitochondrial quality rather than increased biogenesis. SCENITH profiling revealed a metabolic shift from glycolysis toward FAO. Pharmacologic inhibition of CPT1a selectively reduced FAO in CD8 ⁺ T cells and significantly compromised RT-induced antitumor efficacy, despite unaltered glycolytic capacity and overall mitochondrial function. Conclusion: Tumor-intrinsic STING activation drives metabolic rewiring of CD8 ⁺ T cells toward FAO, thereby maintaining mitochondrial fitness and effector function after fractionated RT. The CPT1a–FAO axis constitutes a mechanistic bridge between innate immune sensing and adaptive antitumor immunity, revealing a targetable pathway to enhance combined radiotherapy and immunotherapy. Keywords: STING; fatty-acid oxidation; CD8 ⁺ T cells Proffered Paper 2114 Next-generation radio-immunotherapy for HNSCC using CAR-T cells combined with photon vs. proton irradiation Melike Demir 1 , Ay ş e Sedef Köseer 1,2 , Elke Beyreuther 3,4 , Jörg Pawelke 3,5 , Jordane Divoux 6,7 , Louis- Bastien Weiswald 6,7 , Marion Perreard 6,8 , Mechthild Krause 9,2 , Claudia Arndt 10,11 , Anna Dubrovska 1,12 1 OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany. 2 German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. 3 Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany. 4 Helmholtz Zentrum Dresden-Rossendorf, Dresden, Germany German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Institute of
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