Non-viral siRNA delivery to T cells: Challenges and opportunities in cancer immunotherapy

T lymphocytes are the major drivers of antitumor immunity. The recent clinical success of adoptive T cell therapies and immune checkpoint inhibitors has demonstrated the strength of modulating T cell function in fighting cancer. Nonetheless, a significant fraction of patients remain unresponsive largely due to the immunosuppressive tumor environment that blunts T cell activity. Small interfering RNAs (siRNAs) offer the potential to sequence-specifically silence the expression of negative regulator genes in T cells in a transient manner, thereby releasing the block on anti-tumor responses. Despite the current focus on small molecule- and antibody-based immune checkpoint inhibitors as well as T cell-directed delivery of mRNA and genome editing machinery, the application of siRNA involves important clinical advantages. The recent surge of adoptive cell therapies and development of new and potent delivery approaches has enabled efficient siRNA delivery to T cells both ex vivo and in vivo. As such, siRNA molecules have a newfound potential to improve the proliferation, survival, tumor infiltration and potency of T cells in cancer immunotherapy. In this review, we briefly discuss the extracellular and intracellular delivery hurdles associated with siRNA therapy, in particular with regard to T cell targeting. We provide a timely and comprehensive overview of current and emerging delivery technologies used for siRNA transfection, discussing their strengths and weaknesses from a clinical as well as a manufacturing point-of-view. Finally, we critically review the current status and new potential avenues for modulating T cell function in cancer immunotherapy using siRNA.