Innovative immune checkpoint modulators: monoclonal antibodies, small molecules, non-coding RNAs, and nanoparticles in cancer immunotherapy.

Targeting immune checkpoints through diverse therapeutic platforms has emerged as a promising strategy for cancer immunotherapy, offering improved outcomes compared with conventional chemotherapy. Immune checkpoint pathways are critical regulators in maintaining self-tolerance under physiological conditions; however, their dysregulation within the tumor microenvironment (TME) promotes immune evasion and T-cell exhaustion. Key immune checkpoint receptors, including CTLA-4, PD-1, TIM-3, LAG-3, and TIGIT, function as immunosuppressive agents by downregulating the activation of immune effector cells and have become major therapeutic targets. While monoclonal antibodies (mAbs) remain the cornerstone of immune checkpoint blockade, recent advances have expanded the therapeutic landscape to include small-molecule inhibitors, non-coding RNAs, and nanoparticles. These emerging approaches aim to enhance efficacy, improve tumor penetration, and overcome resistance associated with antibody-based therapies. This review provides a comprehensive overview of both established and emerging strategies involving mAbs, small-molecule inhibitors, non-coding RNAs, and nanoparticles. We describe their mechanisms, current clinical applications, and supporting preclinical and clinical evidence. Additionally, we highlight their potential role in advancing next-generation cancer immunotherapy and address current therapeutic limitations.