CpG‐Based Nanovaccines Enhance Ovarian Cancer Immune Response by Gbp2‐Mediated Remodeling of Tumor‐Associated Macrophages

Abstract CpG oligodeoxynucleotides (CpG), as an immunoadjuvant, can facilitate the transformation of tumor‐associated macrophages (TAMs)into tumoricidal M1 macrophages. However, the accumulation of free CpG in tumor tissues remains a substantial challenge. To address this, a nanovaccine (PLGA‐CpG@ID8‐M) is engineered by encapsulating CpG within PLGA using ID8 ovarian cancer cell membranes (ID8‐M). This nanovaccine demonstrates remarkable efficacy in reprogramming TAMs in ovarian cancer and significantly extends survival in ID8‐bearing mice. Notably, these findings indicate that the nanovaccine can also mitigate chemotherapy‐induced immunosuppression by increasing the proportion of M1‐like TAMs and reducing the expression of CD47 on tumor cells, thereby achieving a synergistic effect in tumor immunotherapy. Mechanistically, through transcriptome sequencing (RNA‐seq), single‐cell RNA sequencing (scRNA‐seq), and mass spectrometry‐based proteomics, it is elucidated that the nanovaccine enhances the expression of Gbp2 and promotes the recruitment of Pin1, which activates the NFκB signaling pathway, leading to the M1 polarization of TAMs. Furthermore, macrophages with elevated Gbp2 expression significantly inhibit tumor growth in both ID8 ovarian cancer and 4T1 breast cancer models. Conversely, targeting Gbp2 diminishes the antitumor efficacy of the nanovaccine in vivo. This study offers an innovative approach to immunotherapy and elucidates a novel mechanism (Gbp2‐Pin1‐NFκB pathway) for remodeling TAMs.