Until recently, inflammatory chemokines were viewed mainly as indispensable “gate keepers” of immunity and inflammation. However, updated research indicates that cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. The CCR5 and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, but extensive studies on the role of the CCL5/CCR axis were performed only in a limited number of cancers. This review summarizes updated information on the role of CCL5 and its receptor CCR5 in cancer cell proliferation, metastasis, and the formation of an immunosuppressive microenvironment and highlights the development of newer therapeutic strategies aimed to inhibit the binding of CCL5 to CCR5, to inhibit CCL5 secretion, or to inhibit the interactions among tumor cells and the microenvironment leading to CCL5 secretion. 1. Introduction Epidemiological and experimental studies provided clear evidence that unresolved pathogen infections and chronic inflammation promote tumor development and led to the inclusion of inflammation among the hallmarks of cancer [1, 2]. On the other hand, cancer cells not only make themselves “invisible” to the immune system, but also favor the formation of an immunosuppressive microenvironment unable to eliminate cancer cells [3]. As a result, the reduced secretion of molecules acting as tumor-promoting factors and the normalization of the tumor microenvironment [4] are main goals to develop appropriate antitumor strategies. The tumor microenvironment is composed of stromal and inflammatory cells that are recruited and/or locally induced to proliferate or differentiate by tumor cells or by normal cells “educated” by tumor cells. They communicate directly through cell-cell contact but also indirectly through paracrine signals [4]. These signals are predominantly constituted by cytokines and chemokines (chemotactic cytokines), key orchestrators of leukocytes trafficking under homeostatic conditions as well as during inflammation and cancer [5] and part of the molecular pathways driving cancer cell survival, motility, and invasiveness [6]. Chemokines, identified on the basis of their ability to induce chemotaxis, have a fundamental role not only in inflammation and immune surveillance but also in cancer progression [7]. Chemokines, secreted by the tumor cells from primary tumors or metastatic sites or by the normal cells recruited
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