Over the past two decades, immunotherapies have emerged as promising treatments for various cancers, with immune checkpoint inhibitors (ICIs) playing a crucial role. Monoclonal antibodies (mAbs) targeting specific immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1), have shown significant clinical efficacy. However, many patients develop resistance or tolerance to these treatments due to tumor immune evasion mechanisms. To address this, researchers are focusing on identifying additional ICIs and synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatments. Recent discoveries include targets like T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). This review discusses the structures of these immune checkpoint molecules and their clinical progress in mAbs targeting them. It highlights the therapeutic potential of these targets and their applications in combination therapies. For instance, PD-1/PD-L1 mAbs have been combined with anti-angiogenic agents, radiotherapy, and chemotherapy to enhance treatment efficacy. CTLA-4 mAbs, such as tremelimumab and ipilimumab, are also used in combination with PD-1/PD-L1 mAbs to improve outcomes. Additionally, emerging ICIs like LAG-3, TIM-3, TIGIT, VISTA, BTLA, and SIRPα mAbs are being explored in clinical trials for treating solid tumors. The review emphasizes the importance of combination therapies and the potential of novel ICIs in overcoming resistance and improving patient outcomes. It also discusses the challenges and future directions in the development of these treatments, including the need for more effective and less toxic approaches.Over the past two decades, immunotherapies have emerged as promising treatments for various cancers, with immune checkpoint inhibitors (ICIs) playing a crucial role. Monoclonal antibodies (mAbs) targeting specific immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1), have shown significant clinical efficacy. However, many patients develop resistance or tolerance to these treatments due to tumor immune evasion mechanisms. To address this, researchers are focusing on identifying additional ICIs and synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatments. Recent discoveries include targets like T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). This review discusses the structures of these immune checkpoint molecules and their clinical progress in mAbs targeting them. It highlights the therapeutic potential of these targets and their applications in combination therapies. For instance, PD-1/PD-L1 mAbs have been combined with anti-angiogenic agents, radiotherapy, and chemotherapy to enhance treatment efficacy. CTLA-4 mAbs, such as tremelimumab and ipilimumab, are also used in combination with PD-1/PD-L1 mAbs to improve outcomes. Additionally, emerging ICIs like LAG-3, TIM-3, TIGIT, VISTA, BTLA, and SIRPα mAbs are being explored in clinical trials for treating solid tumors. The review emphasizes the importance of combination therapies and the potential of novel ICIs in overcoming resistance and improving patient outcomes. It also discusses the challenges and future directions in the development of these treatments, including the need for more effective and less toxic approaches.