We Have Previously Demonstrated that Scavenger Receptor a (SRA) Acts as an Immunosuppressive Regulator of Dendritic Cell (DC) Function in Activating Antitumor T Cells. Here We Investigate the Potential of Inhibiting SRA Activity to Enhance DC-Targeted Chaperone Vaccines Including One that Was Recently Evaluated in Melanoma Patients. We Show that Short Hairpin RNA-Mediated SRA Silencing Significantly Enhances the Immunogenicity of DCs that Have Captured Chaperone Vaccines Designed to Target Melanoma (I.e., Hsp110-Gp100) and Breast Cancer (I.e., Hsp110-HER/Neu-ICD). SRA Downregulation Results in Heightened Activation of Antigen-Specific T Cells and Increased CD8+ T Cell-Dependent Tumor Inhibition. Additionally, Small Interfering RNA (SiRNA) Complexed with the Biodegradable, Biocompatible Chitosan as a Carrier Can Efficiently Reduce SRA Expression on CD11c+ DCs in Vitro and in Vivo. Our Proof-Of-Concept Study Shows that Direct Administration of the Chitosan-SiRNA Complex to Mice Promotes Chaperone Vaccine-Elicited Cytotoxic T Lymphocyte (CTL) Response, Culminating in Improved Eradication of Experimental Melanoma Metastases. Targeting SRA with This Chitosan-SiRNA Regimen Combined with the Chaperone Vaccine Also Leads to Reprogramming of the Tumor Environment, Indicated by Elevation of the Cytokine Genes (I.e., Ifng, Il12) Known to Skew Th1-Like Cellular Immunity and Increased Tumor Infiltration by IFN-Γ+CD8+ CTLs as Well as IL-12+CD11c+ DCs. Given the Promising Antitumor Activity and Safety Profile of Chaperone Vaccine in Cancer Patients, Further Optimization of the Chitosan-SiRNA Formulation to Potentially Broaden the Immunotherapeutic Benefits of Chaperone Vaccine is Warranted.