Abstract / Summary
Therapy resistance, metastatic relapse, and immune evasion are major contributors to breast cancer–related mortality; however, the proteostatic systems that support phenotypic plasticity remain incompletely understood. Chaperone-mediated autophagy (CMA) is a selective lysosomal pathway that degrades individual cytosolic proteins and can reshape cancer signaling, metabolism, and stress responses. The biological effects of this process depend not simply on pathway activity, but on which proteins are accessible to CMA and whether their degradation is completed in a particular cellular context. Here, we organize current evidence around a mechanistic framework that links oncogenic pathways, metabolic and oxidative stress, therapeutic pressure, and microenvironmental signals to changes in substrate accessibility, chaperone recognition, substrate translocation, and lysosomal degradative competence. These regulatory steps determine the fate of specific substrates and influence metabolic reprogramming, treatment response, metastatic adaptation, and tumor–immune interactions across breast cancer subtypes. We also examine the interplay with parallel proteolytic systems and the principal obstacles to clinical application, including pharmacological selectivity, assessment of CMA activity in patient samples, cell-type specificity, and compensatory proteolysis. Rather than classifying CMA as consistently oncogenic or tumor-suppressive, we view it as a context-resolved proteostatic decision node whose function and clinical significance vary according to substrate identity, cellular compartment, disease state, and treatment exposure. This framework may help determine whether CMA inhibition, activation, or substrate-directed degradation is most appropriate for therapeutic investigation in breast cancer.