A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer‐related mortality, with liver metastasis posing a significant therapeutic challenge. Within the “seed and soil” paradigm, disrupting both tumor cells and their supportive microenvironment is essential to suppress disease progression. Here, we utilized single‐cell transcriptomics of clinical CRC samples identified NOX4⁺ (NADPH oxidase 4 positive) cancer‐associated fibroblasts (CAFs) and CXCR4⁺ (C-X-C motif chemokine receptor 4 positive)/GPX4⁺ (glutathione peroxidase 4 positive) tumor cells as critical drivers of metastasis. Consequently, a dual‐targeted nanosystem was thus devised to induce ferroptosis in tumor cells and reprogram CAFs. This strategy integrates a ferroptosis inducer encapsulated within the cancer cell membrane and a CXCR4–NOX4 inhibitor loaded onto a hybrid membrane composed of cancer cells and CAFs, thereby achieving dual synergistic effects: ferroptotic eradication of malignant cells and induction of CAFs quiescence. In orthotopic, liver metastasis, and patient-derived tumor xenograft humanized immune mouse models, these nanoparticles significantly suppressed tumor growth, mitigated immunosuppressive signaling, and augmented antitumor immune responses, while maintaining favorable biocompatibility. These findings highlight the potential of simultaneously targeting ferroptosis in tumor cells and CAFs reprogramming in the tumor microenvironment to overcome liver metastasis of CRC.