Nature Chemical Biology May 2026: TerminaTOR Genetically Encoded Peptide mTORC1 Inhibitor Reveals Nuclear mTORC1 Regulates CCAAT-Motif Gene Transcription in Cancer
A Nature Chemical Biology paper published May 2026 reported TerminaTOR, a genetically encoded peptide inhibitor of mTORC1 that can be targeted to specific subcellular locations and used to dissect mTORC1 biology in living cells. Targeted to the lysosome, TerminaTOR inhibits canonical lysosomal mTORC1 and induces autophagy — recapitulating rapamycin's pharmacology. Targeted to the nucleus, TerminaTOR specifically inhibits nuclear mTORC1 and reveals a previously uncharacterized regulatory function: nuclear mTORC1 controls transcription of CCAAT-motif-containing genes and promotes cancer cell proliferation. The work creates a tool for spatially separating canonical (cytoplasmic) and noncanonical (nuclear) mTORC1 functions and identifies nuclear mTORC1 as a potentially druggable axis distinct from the lysosomal pathway. Therapeutic implication: cancer programs targeting mTORC1 might benefit from nucleus-selective inhibitors that spare lysosomal autophagy.