The VHL tumor suppressor at the crossroad of protein folding, aggregation, and cancer.

Protein aggregation is no longer viewed only as pathological but as a dynamic and reversible regulatory mechanism in cancer. Within the tumor microenvironment, proteins such as the von Hippel-Lindau tumor suppressor protein (pVHL) can transition from a folded state to aggregated states. Mutations, environmental stress, and dysfunctional chaperone systems further promote pVHL aggregation. Structural plasticity enables adaptive responses that support protein storage, cell survival, and dormancy, a reversible state promoting drug resistance and cancer recurrence. Targeting protein aggregation with chemical chaperones and amyloid inhibitors could represent a promising therapeutic strategy to rescue the tumor suppressor activity and overcome dormancy-associated drug resistance. In this review, we address the amyloid aggregation of pVHL, the factors contributing to this behavior, the correlation between protein aggregation and cellular dormancy, and potential therapeutic strategies that bridge protein aggregation and oncology.