Reconfiguration of tumor cells with LCOR transcription factor mRNA nanotherapy to enhance immunotherapy efficacy

Transcription factors (TFs) are generally deemed undruggable due to their structural complexity. mRNA technologies have paved the way to overcome this therapeutic limitation by enabling the development of mRNA protein replacement therapies. Here we explore the newly described TF activity of LCOR (Ligand-dependent corepressor), which suppresses tumor growth by inducing the antigen presentation machinery (APM) of the tumor cells and constrains cellular plasticity. These LCOR effects facilitate recognition of the tumor by the immune system and immune-mediated tumor cell death. To deliverLcormRNA into tumor cells, we have used poly β-(amino esters) (pBAE) nanoparticles (NPs) for local delivery ofLcormRNA in breast cancer primary tumor models. We have engineered pBAE-NPs with high potential for efficiently encapsulate mRNA and facilitate cellular uptake. Our results show optimal endosomal escape, which results in high transfection efficiencyin vitroandin vivo, restoring LCOR function in tumor cells and engaging their APM. In preclinical triple-negative breast cancer (TNBC) models, the intratumoral delivery ofLcormRNA led to a reduction in tumor growth. Importantly, the combination ofLcormRNA-loaded NPs with anti-PDL1 or anti-CTLA4 immunotherapies eradicated most of the tumors in our preclinical TNBC model. Overall, our nanotherapeutic strategy emerges as an innovative TF-replacement therapy, leveraging the immunogenic effects of LCOR to eradicate breast cancer tumors when combined with immunotherapy.