T cells play an important role in cancer immunosurveillance and tumor destruction. However, tumor cells alter immune responses by modulating immune cells through antigen stimulation and immunoregulatory cytokines. A better understanding of the interplay between tumor cells and T cells might provide new strategies to enhance antitumor immunity. Through an antigen-screening approach using colorectal tumor-reactive T cells, we identified an HLA-DR11-restricted T-cell epitope encoded by KIAA0040 as well as MHC-unrestricted human galectin-3 (Gal-3) expressed by tumor cells. Although the biological function of KIAA0040 remains to be determined, we found that Gal-3 functioned as an immune regulator for direct T-cell activation and function. T-cell activation induced by Gal-3 resulted in T-cell apoptosis. We showed that a high level of expression of Gal-3 promoted tumor growth in vitro and in vivo. Using a mouse tumor model, we showed that delivery of high doses of Gal-3 inhibited tumor-reactive T cells and promoted tumor growth in mice receiving tumor-reactive CD8(+) T cells. These findings suggest that Gal-3 may function as an immune regulator to inhibit T-cell immune responses and promote tumor growth, thus providing a new mechanism for tumor immune tolerance.