Liver metastasis is the major cause of colorectal cancer (CRC)-related death, and 1/4 CRC patients present liver metastases at first diagnosis. Despite significant improvements in metastatic CRC, the long-term outcome remains poor. Chimeric antigen receptor (CAR)-T cell therapy represents a powerful strategy with superior efficacy for personalized cancer. Herein, CRC and adjacent non-tumor tissues from patients with liver metastasis were subjected to mass spectrometry (MS) analysis to identify differentially expressed proteins. CD46 was upregulated in CRC tissues, particularly for CRC liver metastasis (CRLM), and critically associated with poor prognosis in different cohorts. Consistently, CD46 promoted aggressive behaviors and liver metastasis ability of CRC cells, indicating that CD46 was a prognostic factor in patients with CRLM. Mechanistically, CD46 transformed T cells into Tregs by binding to the Lcp1, thus protecting CRC cells from immune surveillance. CD46-CAR T cells were constructed and significantly regressed tumors in NCG mice bearing CD46-overexpressed CRC cells, along with little cytotoxicity to CD46-low-expressed cells. Meanwhile, CD46-CAR T cells showed robust antitumor activity in an established PDX xenograft model, which was enhanced by RANTES/IL15 cytokines. Moreover, folic acidmodified magnesium silicate hollow nanospheres containing cytokines IL-2, IL15, and CCL5 (FA_IL/CCL) were designed and exhibited excellent biodegradable and biocompatible properties. FA_IL/CCL efficiently potentiated the immune efficacy of CD46-CAR T cells by suppressing the proliferation and liver metastasis in CD46 highexpressed CRC PDX mice. Collectively, our findings highlight that CD46-CAR T cell therapy may provide a potential in the treatment of human CRLM, nanotherapeutics will potentiate the immune efficacy with good biosafety.