Nanotechnology-Enabled Immunotherapy for Colorectal Cancer: Overcoming the "Cold" Tumor Microenvironment in Microsatellite-Stable Disease

Background

Immune checkpoint inhibitors (ICIs) have transformed the management of mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), yet the ~95% of patients with mismatch repair-proficient/microsatellite-stable (pMMR/MSS) disease derive little benefit owing to an immunologically "cold" tumor microenvironment (TME), poor T-cell infiltration, myeloid dominance, TGF-β-enriched stroma, and the systemically immunosuppressive milieu imposed by hepatic metastases. Clinically tested combinations-multikinase inhibitor plus anti-PD-1, Fc-enhanced dual checkpoint blockade, chemotherapy- or antiangiogenic-ICI regimens-have so far produced modest, largely non-durable response rates that are further attenuated in liver-metastatic disease, motivating approaches that pharmacologically remodel the TME rather than only release checkpoint restraint.