CTLA-4 and PD-1 are immune checkpoint proteins that regulate T-cell activation. Inhibiting these pathways has led to new immunotherapies for melanoma, lung cancer, and other cancers. Ipilimumab (CTLA-4 inhibitor) is approved for melanoma, while nivolumab and pembrolizumab (PD-1 inhibitors) are used for melanoma and non-small cell lung cancer. Combination therapy with ipilimumab and nivolumab is approved for BRAF WT melanoma. CTLA-4 acts early in immune responses, primarily in lymph nodes, while PD-1 acts later, in peripheral tissues. Both inhibit T-cell activation, but their mechanisms differ. CTLA-4 blocks CD28 signaling, while PD-1 binds to its ligands (PD-L1 and PD-L2) to suppress T-cell activity. PD-1 is more broadly expressed on activated T cells, B cells, and myeloid cells. Inhibiting these pathways can restore antitumor immune responses, leading to long-term benefits in some patients. However, immune checkpoint inhibitors can cause immune-related adverse events, such as hypophysitis, which is more common with CTLA-4 inhibitors. PD-1 inhibitors may have a lower incidence of severe side effects. Combining CTLA-4 and PD-1 inhibitors may enhance efficacy by increasing T-cell activation and reducing immunosuppression. Clinical trials show that combination therapy improves response rates and progression-free survival in melanoma and other cancers. However, combination therapy may also increase toxicity. PD-L1 expression on tumor cells and immune cells is associated with response to PD-1 or PD-L1 inhibitors. Biomarkers like PD-L1 expression and mutational load may help predict response to therapy. Immune checkpoint inhibitors have shown significant clinical benefits in melanoma and other cancers, but more research is needed to optimize their use and minimize toxicity. These therapies represent a promising approach to cancer treatment by enhancing the immune system's ability to recognize and destroy tumor cells.CTLA-4 and PD-1 are immune checkpoint proteins that regulate T-cell activation. Inhibiting these pathways has led to new immunotherapies for melanoma, lung cancer, and other cancers. Ipilimumab (CTLA-4 inhibitor) is approved for melanoma, while nivolumab and pembrolizumab (PD-1 inhibitors) are used for melanoma and non-small cell lung cancer. Combination therapy with ipilimumab and nivolumab is approved for BRAF WT melanoma. CTLA-4 acts early in immune responses, primarily in lymph nodes, while PD-1 acts later, in peripheral tissues. Both inhibit T-cell activation, but their mechanisms differ. CTLA-4 blocks CD28 signaling, while PD-1 binds to its ligands (PD-L1 and PD-L2) to suppress T-cell activity. PD-1 is more broadly expressed on activated T cells, B cells, and myeloid cells. Inhibiting these pathways can restore antitumor immune responses, leading to long-term benefits in some patients. However, immune checkpoint inhibitors can cause immune-related adverse events, such as hypophysitis, which is more common with CTLA-4 inhibitors. PD-1 inhibitors may have a lower incidence of severe side effects. Combining CTLA-4 and PD-1 inhibitors may enhance efficacy by increasing T-cell activation and reducing immunosuppression. Clinical trials show that combination therapy improves response rates and progression-free survival in melanoma and other cancers. However, combination therapy may also increase toxicity. PD-L1 expression on tumor cells and immune cells is associated with response to PD-1 or PD-L1 inhibitors. Biomarkers like PD-L1 expression and mutational load may help predict response to therapy. Immune checkpoint inhibitors have shown significant clinical benefits in melanoma and other cancers, but more research is needed to optimize their use and minimize toxicity. These therapies represent a promising approach to cancer treatment by enhancing the immune system's ability to recognize and destroy tumor cells.