Monocyte chemoattractant protein-1 (MCP-1) is a well-known chemokine that binds to the CCR2 receptor and acts as an immunosuppressive factor in the tumor environment. Specifically, MCP-1 recruits and activates tumor associated macrophages (TAMs) which plays a role in tumorigenesis, angiogenesis, and metastasis. Elevated serum levels of MCP-1 in patients have been correlated with advanced stages of cancer and the link between MCP-1, TAMs, and poor prognosis and/or relapse is characteristic to many cancer types including melanoma, breast, myeloma, colon, ovarian, and prostate. Hence, a targeted strategy to block MCP-1/CCR2 binding and the signaling cascade in the tumor microenvironment would provide a multifaceted approach to inhibit tumor progression and may be globally applied across solid tumors and oncology. Towards this effort, since the submission of our first Ming Hsieh proposal last year, the Chung lab, in collaboration with the Kani Gross, and Shen labs, has developed MCP-1 peptide amphiphile micelles (MPAMs) consisting of the CCR2-binding motif of MCP-1 (residues 13-35) for prostate cancer targeting17. The peptide sequence lacks the N-terminal 2- 8 amino acids of MCP-1 which also endowed a pro-apoptotic effect on several prostate cancer cell lines in vitro18. Moreover, we showed and published that the therapeutic potency of MPAMs correlated with the level of cellular CCR2 expression, confirming MPAMs specifically target and bind cancer cells through binding the CCR2 receptor and can be used to directly exert a cytotoxic effect for cancer therapy. In this proposal, we aim to augment our system by Aim 1) incorporating the cell penetrating cytotoxic peptide, KLAKLAK (KLAK) for additional therapeutic, tumoricidal activity of MPAMs to account for the large heterogeneity of CCR2 expression among cancer cells. Aim 2) In addition, since MCP-1 also plays a role in tumor immunosuppression, another goal of this proposal is to also investigate the immunomodulatory potential of MPAMs. If successful, this novel nanomedicine platform will be converted to federally funded and multidisciplinary projects, and testing on clinical samples and settings, with application from cancer to other inflammatory disease.