PIK3CA and cancer: To address the heterogeneity of mTOR involvement across cancers, we propose a working model that links four evidence layers: (i) upstream genetic drivers—most notably PTEN loss and PIK3CA hotspot mutations—feeding into (ii) the pathway’s architectural cores (mTORC1/2; RPTOR/RICTOR/MLST8), (iii) expression-level rewiring centered on translational control (EIF4E–EIF4EBP1–RPS6/RPS6KB1) and nutrient-sensing modules (LAMTOR/AMPK), and (iv) phenotypic outputs (enhanced translation, growth, metabolic reprogramming).