Despite major advances in understanding the mechanisms leading to tumor immunity, a number of obstacles hinder the successful trans-lation of mechanistic insights into effective tumor immunotherapy. Such obstacles include the ability of tumors to foster a tolerant mi-croenvironment and the activation of a plethora of immunosuppres-sive mechanisms, which may act in concert to counteract effective immune responses. Here we discuss different strategies employed by tumors to thwart immune responses, including tumor-induced im-pairment of antigen presentation, the activation of negative costim-ulatory signals, and the elaboration of immunosuppressive factors. In addition, we underscore the influence of regulatory cell popula-tions that may contribute to this immunosuppressive network; these include regulatory T cells, natural killer T cells, and distinct sub-sets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms may be effective in combination with other conventional strategies to over-come immunological tolerance and promote tumor regression.
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