SQSTM1/p62 and Mitochondrial Stress in Triple-Negative Breast Cancer: A Critical Pathology Perspective

Sequestosome 1 (SQSTM1/p62) links autophagy to cellular stress responses and can be assessed by immunohistochemistry. In triple-negative breast cancer (TNBC), however, its staining has no single biological interpretation. This selective narrative review examines human tissue studies alongside experimental evidence, focusing on the pathological assessment of mitochondrial stress. Human evidence remains limited—retrospective cohorts report inconsistent prognostic associations, and treatment-related changes are poorly characterized. Increased p62 can reflect enhanced synthesis or impaired degradation; mitochondrial clearance can also proceed without it. These observations explain why p62 staining alone cannot measure mitophagic flux. We propose assessing p62 distribution and abundance alongside mitochondrial content, oxidative damage and autophagy–lysosomal markers to describe exploratory tissue profiles. Each profile is linked to a proposed mechanism and to findings that would support or challenge that explanation. We consider baseline response associations separately from changes in residual disease, because complete responders lack residual invasive tumor for paired analysis. Mitochondrial turnover, respiratory function and genetic perturbation with rescue offer complementary ways to test the proposed dependencies. This framework provides a basis for investigating the relationship between mitochondrial damage, clearance, recovery and treatment persistence; its clinical relevance remains to be established.