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Background Despite recent advancements in treating advanced non-small-cell lung cancer (NSCLC), limited options exist for patients resistant to immune checkpoint inhibitors (ICI). Ateganosine (THIO; 6-thio-2’-deoxyguanosine) is recognized by telomerase and incorporated into telomeres in cancer cells. Once incorporated, Ateganosine compromises the telomere structure and function, leading to ‘uncapping’ of the chromosome ends and thus resulting in rapid tumor cell death and activation of antitumor immunogenicity.Methods The study ( NCT05208944) includes adults with advanced NSCLC, who had relapsed after 2 prior treatments which had prior ICI, Chemotherapy and Docetaxel. Eligible patients must have histologically confirmed NSCLC and documented progression following prior treatment with at least one line of ICI therapy. Key exclusion criteria include active brain metastases, uncontrolled systemic disease, and prior exposure to THIO. Participants receive THIO followed by cemiplimab administered every 3 weeks. The primary endpoint is overall response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Exploratory endpoints include biomarker analysis and correlation of telomere attrition with clinical outcomes.Results Enrollment is ongoing, with up to 48 patients expected to be recruited across multiple clinical sites in part C of the study. Safety data and preliminary efficacy outcomes will be reported as they become available.Conclusions THIO-101 aims to provide evidence on the potential of THIO to restore sensitivity to ICIs in patients with advanced NSCLC resistant to prior ICI therapies. This trial will asses the feasibility of this novel sequential treatment approach and explore key biomarkers for predicting response.Trial Registration 01-Mar-2022 (Australia) CT-2021-CTN-04933-1 20-Jul-2022 (Hungary) EudraCT Number 2021-005136-34 22-Nov-2022 (Poland) EudraCT Number 2021-005136-34 06-Oct-2022 (Bulgaria) EudraCT Number 2021-005136-34 27-Jul-2023 (United States) IND-163503 02-Dec-2024 (Taiwan) 1139073522 17-Sep-2024 (Turkey) E-661756679-514.02.02-1577145