Because antigen-specific cytotoxic T-lymphocytes (CTLs) are major effector cells in tumor immunity, more efficient delivery of tumor-associated antigens to the major histocompatibility complex class I-presentation pathway in antigen-presenting cells (APCs) will substantially contribute to establish more effective cancer immunotherapy. Herein, we demonstrated that a combinational approach based on the antigen-delivery system using poly(gamma-glutamic acid) nanoparticles (,gamma-PGA NPs) and an endoplasmic reticulum (ER)-transport system containing an ER-insertion signal sequence (Eriss) significantly enhanced the ability of a peptide vaccine to induce cellular immune responses, including CTL activity. Immunization with gamma-PGA NPs entrapping Eriss-conjugated antigenic peptides markedly amplified and activated CTLs and interferon-gamma-secreting cells specific for the antigen, whereas no cellular immune responses were detected following vaccination with only one of the systems alone. Our data provide evidence that efficient delivery of antigenic peptides into APCs, as well as active ER-translocation of antigenic peptides in APCs should be considered in the development of peptide-based cancer immunotherapy. (C) 2007 Elsevier Inc. All rights reserved.