Reprogramming tumor cells with LCOR mRNA nanotherapy to enhance immunotherapy.

Transcription factors (TFs) are often considered undruggable due to their structural complexity. mRNA technologies can overcome this therapeutic limitation by enabling dynamic protein replacement therapies. Here, we explore the TF activity of LCOR (Ligand-dependent corepressor), which suppresses tumor growth, at least in part by inducing the antigen presentation machinery (APM) in tumor cells and constraining cellular plasticity. These effects facilitate tumor immune recognition and immune-mediated tumor eradication. We used poly β-(amino esters) (pBAE) nanoparticles (NPs) for local delivery of Lcor mRNA in multiple breast cancer models. pBAE-NPs efficiently encapsulate mRNA and facilitate cellular uptake, achieving optimal endosomal escape, resulting in high transfection efficiency in vitro and in vivo, restoring LCOR function in tumor cells and engaging their APM. In preclinical models, intratumoral delivery of Lcor mRNA reduced tumor growth. Importantly, the combination of Lcor mRNA-loaded RH-pBAE-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 in a lock-in/wipe-out fashion, leveraging the immunogenic effects of LCOR to eradicate breast cancer tumors when combined with immunotherapy.