(Un-)Known Chances: Emerging Hope for Cancer of Unknown Primary - Highlights from ESMO 2025 and the first International Cancer of Unknown Primary Meeting.

Cancer of unknown primary (CUP) accounts for 1-3% of newly diagnosed cancers. For decades, management has relied on empirical platinum-based chemotherapy, which offers a poor prognosis with a median overall survival typically below one year. However, data from the ESMO 2025 Congress and the International Cancer of Unknown Primary Meeting (ICUPM) signal a transformative shift in the field. This review synthesises current and upcoming data on integrative genomic profiling, liquid biopsy-based tissue-of-origin prediction, functional imaging, and tumour-agnostic therapeutic strategies in CUP. Together, these advances support redefining CUP as a molecularly stratifiable disease requiring early comprehensive profiling and multidisciplinary interpretation to improve outcomes.