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CUP is a relatively common diagnosis that accounts for 3-9% of all cancers. The prognosis is poor with median survival of approximately 9 months. The identification of the primary tumor and therapy targets could improve the survival of these patients. We employed the BostonGene Tumor PortraitTM platform to interrogate 19 CUP cases. Trained on >19,000 samples and validated on 28,000 samples from independent datasets, the machine-learning based algorithm integrates whole-exome and RNA sequencing (WES and RNAseq) analysis to characterize cancer drivers, the tumor microenvironment, potential targets, tumor composition, molecular signatures, and site of origin (94% sensitivity and 99% specificity). The predicted tissue of origin was considered acceptable when it was compatible with tumor histopathology and immunoprofile, and included in the differential diagnosis of radiologic studies. The discovered biomarkers and possible treatments were discussed during our multidisciplinary precision oncology meeting. 16 out of 19 CUP cases (84%) had an acceptable predicted tissue of origin. Two cases lacked clinical evidence to support the predicted primary tumor, and 1 case failed RNAseq. Lung accounted for most of the sites of origin (31%) followed by gastrointestinal (15%) and breast cancers (8%). Other diagnoses included melanoma, uterine, bladder, and renal carcinomas, among others. Except for one case, a clinically significant biomarker or target was found. Those included relevant mutational signatures (e.g., homologous recombination deficiency, DNA mismatch repair), genetic characteristics (high tumor mutational burden (TMB), microsatellite instability), activating alterations (FGFR1, MYC, ERBB2 amplifications; NCOA4::RET fusion), loss of function in tumor suppressor genes (TP53, FANCA, ATM), and gene overexpression (ER). Further, microenvironment analysis characterized the tumor immune infiltrate and the level of RNA expression of PD-L1, PD-L2, and CTLA4. These oncology biomarkers and potential targets are of significant value independent of tissue of origin. In addition, mutations in NF1, KRAS, TP53, MSH2, BRCA1, and PTEN were found and validated by commercially available targeted NGS panels. Based on CUP tumor profiling by this platform, positive treatment response has been observed in 3 out of 4 CUP patients thus far, e.g., one patient with metastatic disease that showed high TMB and immune infiltrated microenvironment treated with Ipilimumab and Nivolumab had a sustained response. Therapy in oncology is often determined by the tissue origin, making CUP a therapeutic challenge. In this study, we demonstrate the application of an integrative WES and RNAseq platform to not only predict the site of origin, but also to identify relevant biomarkers and therapeutic targets in CUP. Citation Format: Majd Al Assaad, Michael Sigouros, Jyothi Manohar, Daniela Guevara, Zoia Antysheva, Daria Kiriy, Alexandra Boyko, Naira Samarina, Nara Shin, Viktor Svekolkin, Svetlana Podsvirova, Noel English, Alaina Villarreal, Brianna McKenna, Cagdas Tazearslan, Diana Shamsutdinova, Vladimir Kushnarev, Troy Kane, David Wilkes, Manish Shah, Barbara Ma, Scott T. Tagawa, David Nanus, Jones Nauseef, Olivier Elemento, Juan Miguel Mosquera, Cora N. Sternberg. Cancer of unknown Primary (CUP): Beyond the identification of the site of origin by an integrative genomic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2143.