Getngliosides are one of the immunosuppressive molecules released by tumors to their microenvironment. These glycosphingolipids are differentially distributed in tumoral vs. normal tissues, and gangliosides containing an N- glycolylated variant of sialic acid have been found to be preferentially tumor-associated in humans. One such ganglioside is N-glycolyl GM3 (NGcGM3), which has become an attractive target for antigen-specific antitumor therapy. Since the differential expression of this ganglioside in advanced human tumors contrasts with the trend towards reduced immunogenicity typical of cancer cells, it has been presumed that this molecule plays an important role in tumor biology. Therefore, we have studied the relevance of NGcGM3 for tumoral development and, specially, its influence on the immune response. Our results show that NGcGM3 contributes to tumoral progression by modifying helper T lymphocyte function. This ganglioside reduces the expression of CD4 in T lymphocytes, inserting into the plasma membrane of these cells. Furthermore, it affects cell proliferation and promotes a differentiation towards an anti-inflammatory cytokine secretion profile in CD4+CD25- T lymphocytes. The latter effect is not caused by increased suppression mediated by naturally occurring regulatory T lymphocytes. Additionally, NGcGM3 also affects the differentiation and maturation of dendritic cells.