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

Abstract 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.