The coexistence of spontaneous tumor antigen-specific immune T cell responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction and exhaustion. We have previously observed in patients with advanced melanoma that NY-ESO-1-specific CD8+ T cells upregulate PD-1 and a fraction of PD-1+ NY-ESO-1-specific CD8+ T cells upregulates Tim-3. We have found that Tim-3+PD-1+ NY-ESO-1-specific CD8+ T cells represent highly dysfunctional T cells. Importantly, Tim-3 and PD-1 pathway blockades synergized to enhance immune functions of NY-ESO-1-specific CD8+ T cells upon prolonged antigen stimulation. Whether the upregulation of PD-1 and Tim-3 is associated with tumor antigen-specific CD4+ T cell dysfunction remains unknown. Here, our findings in advanced melanoma patients show that in contrast to virus-specific and total CD4+ T cells, PD-1 and Tim-3 expression is upregulated by NY-ESO-1-specific CD4+ T cells. Interestingly, PD-1 and Tim-3 pathway blockades synergized to restore the numbers of cytokine-producing and proliferating NY-ESO-1-specific CD4+ T cells. Collectively, our findings support the use of Tim-3 and PD-1 pathway blockades to reverse tumor-induced CD8+ and CD4+ T cell exhaustion in patients with advanced melanoma. Our findings have significant implication in terms of novel immunotherapeutic strategies aiming at promoting T cell-mediated tumor regression in patients with advanced cancers.