Cancer without a map: Navigating cancer of unknown primary through molecular profiling

Cancer of unknown primary (CUP) is a heterogeneous group of rare metastatic malignancies that lack an identifiable primary site. Molecular profiling has emerged as a tool to improve diagnostic accuracy, identify actionable alterations, and guide therapy. Relevant literature was identified through searches of PubMed, Scopus and Web of Science. We focused on tissue-of-origin (TOO) prediction, prognostic biomarkers, molecularly targeted therapy, and immunotherapy, synthesizing findings of clinical trials, meta-analyses, and cohort studies. Molecular analyses ranging from single‑gene assays to integrated multi‑omics (genomics, transcriptomics, proteomics and epigenomics) surveys enhance TOO determination, detect actionable DNA alterations and therapy selection. TOO-directed therapy has shown mixed survival benefit; however, integrating molecular data with clinical and pathological evaluation via multidisciplinary tumor boards seem to improve outcomes. Comprehensive genomic profiling enables targeted therapy for patients with actionable alterations such as MSI-high, TMB-high, BRAFV600E, NTRK, or RET fusions. Immunotherapy has shown promising activity, especially in biomarker-selected subgroups, although the predictive criteria remain heterogeneous. Molecular profiling is increasingly central in CUP management, supporting both diagnostic clarification and individualized treatment. Evidence indicates that molecularly guided therapy, particularly when integrated with clinicopathological data, can improve survival and expand treatment options beyond empirical chemotherapy. Future research should aim to optimize biomarker-driven strategies, standardize predictive assays, and improve access to advanced molecular diagnostics.