表达 IRF8 或 NIK 的免疫重塑型 mRNA 在多种癌症模型中产生持久的抗肿瘤免疫

Although immunotherapy has benefited a subset of persons with cancer, its broader efficacy remains limited, primarily because of an immunosuppressive tumor microenvironment characterized by insufficient numbers of functional tumor-specific T cells, antigen-presenting cells (APCs) and tumor-infiltrating lymphocytes.

Here we engineer immune cells in the tumor microenvironment using lipid nanoparticles (LNPs) to deliver immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase or interferon regulatory factor 8. These IR-mRNAs activate APCs in tumors, significantly increasing activated type 1 conventional dendritic cells, immunostimulatory cytokines and priming antitumor CD8 + T cells.

IR-mRNAs encapsulated in LNPs elicited durable antitumor responses in multiple syngeneic mouse tumor models through both intratumoral and intravenous delivery. Coadministration of IR-mRNA and ovalbumin mRNA elicited a ~10-fold increase in antigen-specific CD8 + T cell responses, sustained long-term memory and effectively prevented tumor growth in vaccinated mice.

Additionally, coadministration of IR-mRNA and hemagglutinin mRNA enhanced the humoral response ~5-fold and the cellular response ~15-fold, underscoring their potential as adjuvants for boosting adaptive immunity.