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The complex environment of the mammalian nucleus is compartmentalized into functional units by membraneless organelles. Recent advancements have elevated nuclear speckles, one of the most prominent nuclear condensates, to a central role in gene expression regulation. In their recent paper, Alexander and colleagues provide insights into the involvement of nuclear speckles in cancer progression. They identify two signatures of speckle transcriptome that stratify human cancers and, in the case of the clear cell renal cell carcinoma (ccRC), strongly correlate with drug response and ultimately with patient's survival. These signatures correspond to different morphological states of nuclear speckles and influence speckle-regulated gene expression. A deeper look into transcriptional regulation allowed the authors to identify an amino acid sequence which enables the central transcription factor responsible of ccRC oncogenesis to bring its chromatin target into nuclear speckle proximity. The findings provide new insights into the intricacies of nuclear speckle biology and offer new avenues for understanding cancer progression and developing targeted therapies.