Liposomal Delivery of an Immunostimulatory CpG Induces Robust Antitumor Immunity and Long‐Term Immune Memory by Reprogramming Tumor‐Associated Macrophages

Tumor-associated macrophages (TAMs)-representative immune-suppressive cells in the tumor microenvironment (TME)-are known to promote tumor progression and metastasis, and thus are considered an attractive target for cancer therapy. However, current TAM-targeting strategies are insufficient to result in robust antitumor efficacy. Here, a small lipid nanoparticle encapsulating immunostimulatory CpG oligodeoxynucleotides (SLNP@CpG) is reported as a new immunotherapeutic modality that can reprogram TAMs and further bridge innate-to-adaptive immunity. It is found that SLNP@CpG treatment enhances macrophage-mediated phagocytosis of cancer cells and tumor antigen cross-presentation, and skews the polarization state of macrophages in vitro. Intratumoral injection of SLNP@CpG into an established murine E.G7-OVA tumor model significantly suppresses tumor growth and considerably prolongs survival, completely eradicating tumors in 83.3% of mice. Furthermore, tumor-free mice resist rechallenge with E.G7-OVA cancer cells through induction of immunological memory and long-term antitumor immunity. SLNP@CpG even exerts antitumor efficacy in an aggressive B16-F10 melanoma model by remodeling TME toward immune stimulation and tumor elimination. These findings suggest that, by modulating the function of TAMs and reshaping an immunosuppressive TME, the SLNP@CpG nanomedicine developed here may become a promising immunotherapeutic option applicable to a variety of tumors.