The PLGA-CpG@ID8-M nanovaccine overcomes free CpG accumulation, reprograms TAMs to tumoricidal M1 macrophages via Gbp2/Pin1–NFκB signaling, inhibits tumor growth, and counteracts chemotherapy-induced immunosuppression by boosting M1 TAMs and lowering tumor CD47. This evidence concerns the gene GBP2 and neoplasm.