Lysosomal-stress-driven cargo-fate switching between autophagic degradation and small extracellular vesicle release in triple-negative breast cancer: a hypothesis and theory article.

Triple-negative breast cancer (TNBC) cells face metabolic, proteotoxic and treatment-associated stress, but the mechanisms that determine how stressed cells dispose of intracellular cargo remain incompletely defined. We hypothesize that lysosomal stress shifts part of the autophagy-associated cargo burden from intracellular degradation towards extracellular release in small extracellular vesicle (sEV)-enriched fractions. The rationale integrates general evidence linking autophagy with EV biology with two model-specific observations: RIP1 involvement in Manzamine A-induced secretory autophagy in breast cancer cells and RASAL2-dependent modulation of Rab27a activity and autophagy-associated sEV release in MDA-MB-231 cells. These observations motivate the hypothesis but do not establish its generality across TNBC backgrounds or forms of lysosomal stress. We therefore regard RIPK1 as a candidate regulator whose role may depend on the stress context, whereas the RASAL2-Rab27a module is functionally supported but mechanistically unresolved. The model predicts that perturbing these components will alter time-resolved paired intracellular and extracellular measurements. A coordinated sequence of lysosomal and autophagic changes preceding vesicle-associated export, together with exclusion of cell-death-associated particle release, would support the model; stressor-restricted, arm-specific or injury-associated outcomes would require its revision.