Macrophage-hitchhiking nanomedicine codelivering gemcitabine and KRAS G12D inhibitor orchestrates chemo-immunotherapy for metastatic colorectal cancer.

KRAS G12D-mutant metastatic colorectal cancer (mCRC) presents a formidable clinical challenge due to profound immunotherapy resistance and poor drug delivery to metastatic lesions. In this contribution, we report a macrophage-hitchhiking micellar nanomedicine (GemkiM) that exploits peritoneal macrophage chemotaxis to selectively deliver a KRAS G12D inhibitor and a gemcitabine prodrug to mCRC lung metastases. Beyond targeted delivery, GemkiM at an optimal drug ratio demonstrated interplay of apoptosis and ferroptosis in CT26 colorectal cancer cells, which triggered extensive DNA damage and cGAS-STING activation, promoting immunogenic cell death (ICD). This cascade reversed the "cold" metastatic tumor microenvironment and restored responsiveness to immune checkpoint blockade. Notably, GemkiM targeted CT26 lung metastases via hitchhiking peritoneal macrophages. In a stringent lung-metastatic CRC model, GemkiM elicited substantial tumor inhibition and systemic anti-tumor immunity, which effectively instigated the anti-PD-1 immune checkpoint blockade therapy, leading to a 50% cure rate. This work underscores that targeted chemo-immunotherapy with GemkiM via macrophage-mediated transport might offer a unique therapeutic strategy for overcoming KRAS-driven metastatic cancer.