Cancer immunosurveillance involves a complex interplay between malignant cells and the tumor microenvironment, composed of infiltrating immune cells and tumor-supporting stromal cells. Unraveling these interactions will help increasing our understanding of oncogenesis and may provide new targets for improved therapies. We have discovered that iNKT cells control the progression of mouse prostate cancer by differentially modulating tumor-associated macrophages endowed with pro- and anti-tumor functions. The mechanisms by which iNKT cells support anti-tumor, pro-inflammatory M1-like tumor associated macrophages (TAMs) and restrain pro-tumor, pro-angiogenic M2-like TAMs will be discussed, together with the use of iNKT cells for the therapeutic reprogramming of the tumor microenvironment.