Immune checkpoint inhibitors (ICIs) have shown great promise as immunotherapy for restoring T cell function and reactivating anti-tumor immunity. The US Food and Drug Administration (FDA) approved the first immune checkpoint inhibitor, ipilimumab, in 2011 for advanced melanoma patients, leading to significant improvements in survival rates. Subsequently, other immune checkpoint-targeting antibodies were tested. Currently, seven ICIs, namely ipilimumab (anti-cytotoxic T lymphocyte-associated protein 4 [CTLA4]), pembrolizumab, nivolumab (anti-programmed cell death protein 1 [PD-1]), atezolizumab, avelumab, durvalumab, and cemiplimab (anti-PD-L1), have been approved for various cancer types. However, the efficacy of antibodies targeting CTLA4 or PD-1/programmed death-ligand 1 (PD-L1) remains suboptimal. Consequently, ongoing studies are evaluating the next generation of ICIs, such as lymphocyte activation gene-3 (LAG3), T cell immunoglobulin and mucin-domain containing 3 (TIM3), and T cell immunoglobulin and ITIM domain (TIGIT). Our review provides a summary of clinical trials evaluating these novel immune checkpoints in cancer treatment. Full article:https://www.cell.com/molecular-therapy-family/oncology/fulltext/S2950-3299(24)00015-8