Engineered Nanomicelles Prevent Colorectal Liver Metastasis via Inhibiting the Premetastatic Niche and Regulating the Metabolic Homeostasis

Colorectal liver metastasis is one of the major causes of poor survival in colorectal cancer patients as it causes organ dysfunction and disrupts metabolic homeostasis. Apart from the primary tumor microenvironment (TME) challenges arising from cell proliferation, immunosuppression, and angiogenesis, premetastatic niches also represent an attractive therapeutic target for preventing liver metastasis. Here, we present the engineering of a unique, highly stable sub-100 nm three-drug-loaded nanomicelles (TDC NMs) system carrying the antiproliferative drug gemcitabine, the antiangiogenic drug combretastatin A4, and the anti-inflammatory drug dexamethasone. TDC NMs mitigate tumor progression in syngeneic, xenograft, orthotopic, and metastatic tumors. In-depth quantification of the changes in immune cells revealed that TDC NMs promote T-cell-mediated antitumor immunity, limit the infiltration of protumorigenic MDSCs, and enhance the antitumorigenic M1 population. TDC NMs could also reduce tumor progression, restore abdominal circumference, and normalize ascites fluid formation in orthotopic and metastatic colon cancer models. We further demonstrated that TDC NMs inhibit the formation of premetastatic niches by targeting MDSCs and macrophages, thereby achieving metabolic homeostasis. This study provides a promising therapeutic strategy for mitigating primary tumors and premetastatic niches and can therefore be explored further in colorectal cancer patients.