Achievement of potent immunoresponses against self/tumor antigens and effective therapeutic outcome against advanced tumors remain major challenges in cancer immunotherapy. The specificity and efficiency of two nanoparticle-based delivery systems, lipid-calcium-phosphate (LCP) nanoparticle (NP) and liposome-protamine-hyaluronic acid (LPH) NP, provide us an opportunity to address both challenges. A mannose-modified LCP NP delivered both tumor antigen (Trp 2 peptide) and adjuvant (CpG oligonucleotide) to the dendritic cells and elicited a potent, systemic immune response regardless of the existence or the stage of tumors in the host. This vaccine was less effective, however, against later stage B16F10 melanoma in a subcutaneous syngeneic model. Mechanistic follow-up studies suggest that elevated levels of immune-suppressive cytokines within the tumor microenvironment, such as TGF-β, might be responsible. We strategically augment the efficacy of LCP vaccine on an advanced tumor by silencing TGF-β in tumor cells. The delivery of siRNA using LPH NP resulted in about 50% knockdown of TGF-β in the late stage tumor microenvironment. TGF-β down-regulation boosted the vaccine efficacy and inhibited tumor growth by 52% compared with vaccine treatment alone, as a result of increased levels of tumor infiltrating CD8+ T cells and decreased level of regulatory T cells. Combination of systemic induction of antigen-specific immune response with LCP vaccine and targeted modification of tumor microenvironment with LPH NP offers a flexible and powerful platform for both mechanism study and immunotherapeutic strategy development.