Rewiring Metal-Dependent Cell Death to Unlock Immunotherapy in Colorectal Cancer.

Abstract

Immune checkpoint blockade (ICB) shows limited efficacy in colorectal cancer (CRC), particularly in microsatellite-stable tumors characterized by an immunologically "cold" microenvironment. Notably, the high metabolic demand for copper and iron in CRC, together with metal overload-associated PD-L1 upregulation, makes cuproptosis and ferroptosis attractive targets to enhance ICB responsiveness. Here, we present a laser-activated lipid nanoplatform, CuFeS₂-CA-DAC-Lipo (CCDL), that orchestrates cuproptosis, ferroptosis, and pyroptosis while remodeling the tumor immune microenvironment. CuFeS₂ functions as a near-infrared II photothermal transducer and a source of copper and iron ions, inducing concurrent cuproptosis and ferroptosis via ion overload. Decitabine restores gasdermin E expression to couple oxidative stress with caspase-3-mediated pyroptosis, while chlorogenic acid repolarizes tumor-associated macrophages toward a pro-inflammatory phenotype. This coordinated multimodal cell-death cascade establishes a self-amplifying immunogenic circuit that suppresses tumor growth, sensitizes CRC to ICB, and elicits systemic antitumor immunity.