Solid organ transplantation has revolutionized the treatment of end-stage diseases, yet long-term graft survival remains constrained by immune-mediated injury and the limitations of conventional immunosuppression. Among intracellular pathways that translate alloimmune recognition into cellular activation and tissue remodeling, the mechanistic target of rapamycin (mTOR) has emerged as a central regulator of immune cell differentiation, endothelial function, and fibroproliferative responses. Evidence from kidney, heart, liver, and lung transplantation (LTx) implicates dysregulated mTOR signaling in acute cellular and humoral rejection (ACR and AMR) as well as chronic rejection. These observations highlight the importance of understanding molecular mechanisms to refine diagnostics and guide more precise therapeutic strategies targeting mTOR. In LTx, ACR, AMR and chronic rejection converge on shared downstream processes-metabolic reprogramming, endothelial dysfunction, and fibroproliferative remodeling-where mTOR appears pivotal. Pharmacologic inhibitors such as sirolimus and everolimus modulate T- and B-cell activation and limit structural cell proliferation, yet clinical outcomes remain inconsistent, reflecting incomplete knowledge of context-specific mTORC1/2 activation and the lack of validated in vivo biomarkers. Phosphorylated S6 ribosomal protein (p-S6RP) represents a tissue-based readout of mTORC1 activity and a promising biomarker; extending analyses to additional components (p-4EBP1, p-AKT) and integrating multiplex imaging with artificial intelligence could define reproducible "mTOR activation signatures" across cell types and rejection phenotypes. Such biomarker-driven frameworks may enable refined risk stratification and identify patients most likely to benefit from mTOR-targeted therapies. Together, these insights support a shift from empiric immunosuppression toward precision, pathway-guided interventions, positioning mTOR inhibition within a personalized, biology-driven approach to LTx.
