Driving proteomic imbalance in malignancy provokes proteomic catastrophe and confers tumor suppression.

Unlike genomic instability, the role of proteomic instability in cancer remains poorly defined. Heat shock factor 1 (HSF1), a master regulator of the proteotoxic stress response, preserves proteome integrity under stress and is increasingly recognized as an oncogenic enabler. In Neurofibromatosis type I (NF1)-deficient malignant peripheral nerve sheath tumor (MPNST) cells, HSF1 loss induces widespread protein polyubiquitination, aggregation, and tumor-suppressive amyloidogenesis, yet is dispensable in non-transformed Schwann cells. Mechanistically, HSF1 protects the mitochondrial chaperone HSP60 from toxic soluble amyloid oligomers. To adapt to compromised protein quality, HSF1-deficient MPNST cells activate JNK to repress mTORC1-dependent translation, reducing protein load. Stimulating mTORC1 in these HSF1-deficient cells drives catastrophic proteomic imbalance, triggering pronounced cell death, in part through unchecked amyloidogenesis, and suppressing tumor growth in vivo. Thus, HSF1 safeguards the cancer proteome, enabling the oncogenic capacity of mTORC1. This proof-of-principle study establishes the induction of proteomic catastrophe as a new paradigm for combating malignancy.