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It has been about thirty years since identifying the target of rapamycin and using mTOR inhibitors in organ transplantation. There was a promise that they would replace calcineurin inhibitors with fewer nephrotoxic effects and better graft survival. Unfortunately, with time, the enthusiasm for using them in transplantation decreased due to the unpleasant profile of adverse events and limited evidence of tangible clinical benefit.

With more understanding of physiology and judicious clinical application, new venues for mTOR inhibitors emerged. The mTOR pathway regulates primary cellular functions, including cell growth, metabolism, proliferation, and survival, and is critical for autophagy induction. Thus, as a master regulator, mTOR inhibitors emerged as anticancer therapies. In addition, such action proved beneficial for native or post-transplant malignancies.

Signaling through components of the mTOR pathway is an essential regulator of normal cardiac growth and pathological hypertrophy. mTOR inhibitors are effective in reducing left ventricular thickness and mass. It could be an add-on benefit in kidney transplant recipients with high cardiovascular risk or attenuate cardiac allograft vasculopathy in heart transplant recipients.

The mTOR inhibitors may help manage viral infections like cytomegalovirus, human herpesvirus 8-related Kaposi sarcoma, and possibly the BK virus. Furthermore, the mTOR pathway is modulated in many RNA viruses. Based on these facts, the idea of using mTOR inhibitors to treat COVID-19 infection has been evaluated. Accordingly, a new therapeutic role for mTOR inhibitors for treating COVID-19 infection t has emerged through reducing viral replication, and autophagocytosis, improving T cells function and preventing cytokine storm.

This paper will review these applications of mTOR inhibitors beyond the horizon of transplant immunosuppression.