siRNA-mediated mismatch repair disruption synergizes with oxaliplatin to restore immune surveillance in microsatellite-stable colorectal cancer

Abstract

Proficient mismatch repair/microsatellite-stable colorectal cancer (pMMR/MSS CRC), which represents the majority of clinical cases, exhibits low tumor mutational burden and minimal responsiveness to immune checkpoint blockade. Disrupting the MMR system has been shown to resensitize pMMR/MSS CRC to immune surveillance; however, direct MMR inhibitors are currently unavailable. Here, we bridge this gap by developing small interfering RNA lipid nanoparticles (siMMR@LNPs) capable of silencing key MMR genes, including MLH1, MSH2, and MSH6, achieving over 70% gene silencing in both subcutaneous and hepatic metastatic tumor models of pMMR/MSS CRC. A synergetic strategy combining siMMR@LNPs with oxaliplatin substantially bolsters tumor mutational burden, thereby expanding the tumor mutation-derived neoantigenic peptide repertoire in pMMR/MSS CRC and promoting CD8 + T cell infiltration and activation. This combinatorial regimen effectively inhibits tumor progression in pMMR/MSS CRC across both subcutaneous and liver metastasis mouse models, showing potential to reinstate immune surveillance in the immunotherapy-refractory pMMR/MSS CRC. This approach may offer a viable route to develop a promising immunotherapy for pMMR/MSS CRC.