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 supp...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 tran-scriptomics 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 induc-tion 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.展开更多
基金supported by the Guangdong Province Natural Sci-ence Foundation(2024A1515012061)the Key Clinical Research Proj-ect of Southern Medical University(LC2019ZD011)+4 种基金the Guangdong Basic and Applied Basic Research Foundation(2022A1515110270)the Natural Science Foundation of Jiangsu Province(BK20240466)the China Postdoctoral Science Foundation(2024M763181)the Excellent Postdoctoral Program in Jiangsu Province(2024ZB076)the Guangdong Provincial Key Laboratory of Digital Medicine and Biome-chanics(2023B110008).
文摘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 tran-scriptomics 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 induc-tion 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.
