Previously, we have reported a lipid-based Trp2 peptide vaccine for immunotherapy against melanoma. The suppressive immune microenvironment in the tumor is a major hurdle for an effective vaccine therapy. We hypothesized that curcumin (CUR) would remodel the tumor microenvironment to improve the vaccine activity. Curcumin-polyethylene glycol conjugate (CUR-PEG), an amphiphilic CUR-based micelle, was delivered intravenously (i.v.) to the tumor. Indeed, in the B16F10 tumor-bearing mice, the combination of CUR-PEG and vaccine treatment resulted in a synergistic antitumor effect (P < 0.001) compared to individual treatments. In the immune organs, the combination therapy significantly boosted in vivo cytotoxic T-lymphocyte response (41.0 ± 5.0% specific killing) and interferon-γ (IFN-γ) production (sevenfold increase). In the tumor microenvironment, the combination therapy led to significantly downregulated levels of immunosuppressive factors, such as decreased numbers of myeloid-derived suppressor cells and regulatory T cells (Treg) cells and declined levels of interleukin-6 and chemokine ligand 2-in correlation with increased levels of proinflammatory cytokines, including tumor necrosis factor-α and IFN-γ as well as an elevation in the CD8(+) T-cell population. The results indicated a distinct M2 to M1 phenotype switch in the treated tumors. Combining CUR-PEG and vaccine also dramatically downregulated the signal transducer and activator of transcription 3 pathway (76% reduction). Thus, we conclude that CUR-PEG is an effective agent to improve immunotherapy for advanced melanoma.