Local delivery of MPN/CpG effectively inhibits tumor growth in a B16 melanoma‐bearing mouse model, reshaping the tumor microenvironment (TME) by repolarizing M2‐type tumor‐associated macrophages (TAMs) to an M1‐type and boosting intra‐tumoral infiltration of CD8+/CD4+ T lymphocytes and DCs. Here, CD4 is linked to neoplasm.