Nanodrug modified with engineered cancer cell membrane targets CDKs to activate PD-L1 antibody immunotherapy against liver metastasis of immune-desert colon cancer

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the MSS/pMMR subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Thus, turning the tumor microenvironment immunologically hot is critical for activating a potent immunotherapy through immune checkpoint blockade (ICB) in this unique subtype accounting for 85% cases of total colon cancer. Here, a multifunctional nanodrug (NP-D@MP) carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody to boost the ICB-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modified the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. The nanodrug boosted the immunogenicity of tumor microenvironment, thus improving response rate of PD-L1 antibody treatment. First, CDK inhibitor (CDKi) delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells (TAMCs) sensitizing ICB therapy in CCLM of murine CT26 cell. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft (PDX) model and the patient-derived organoid (PDO) model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the TIME, and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.