e14525 Background: Unprecedented advantages in cancer treatments with immune checkpoint inhibitors (ICI) remain limited to a subset of patients, with high demands for development of better biomarkers to access likely clinical response in advance of ICI therapeutic interventions. 3D genomics has emerged as a novel molecular biomarker modality with strong functional correlation to clinical outcomes (1). The last few years have seen rapid emergence of 3D genomics applications in clinical stratifications. They have demonstrated high sensitivity and specificity in patient stratifications, offered solutions in symptomatic and pre-symptomatic diagnosis, in prognosis, residual disease monitoring, and prediction of response to therapeutic interventions (2-8). EpiSwitch is a 3D genomic platform that has been reduced to practice for the discovery of 3D genomic blood-based biomarkers in a variety of immune-related and oncological diseases (7,8). Methods: A clinical blood assay based on 8 markers - Checkpoint Inhibitor Response Test (CiRT) - has been developed to predict response to PD-(L)1 immune checkpoint inhibition from over 30 million data points, with validations on several independent cancer patient cohorts. The predictive 8 biomarker set is based on an observational clinical trial and several retrospective cohorts, representing all together 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in over 15 diverse oncological indications, i.e. melanoma, lung, urethral, hepatocellular, bladder, prostate, head and neck, colon, breast, bone, brain, lymphoma, larynx. Results: CiRT has demonstrated high accuracy up to 85%, sensitivity of 93% and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach could be successfully utilized for development of a non-invasive predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients. CiRT can assist in treatment decisions, help improve patient selection for optimized treatment, utilize alternative effective treatments, minimize unnecessary toxicity, and efficiently manage the costs.