Targeting Immune Checkpoints: Basic Signaling Pathways and Clinical Translation in Cancer Therapeutics

Immune checkpoints, the key gatekeepers of immune homeostasis, have become the central targets of modern cancer immunotherapy. These regulatory pathways, composed of co-suppressive and co-stimulatory molecules, enable the immune system to distinguish between self and non-self while preventing excessive tissue damage. However, tumor cells strategically block these protective mechanisms through aberrant expression of checkpoint ligands, creating an immunosuppressive microenvironment that promotes tumor immune evasion and metastatic progression. Yet, immune checkpoint therapy is not universally applied due to its specific mechanisms. This review systematically describes the immune checkpoints that function on various types of immune cells, as well as their molecular structure and functional diversity, and elucidates their role in achieving tumor immune escape. We analyze the clinical translation of immune checkpoint inhibitors (ICIs) and their combination therapies. In addition, we combine preclinical findings with clinical trial data to provide a comprehensive framework for understanding the mechanisms of action and clinical applications of immune checkpoints, as well as to present the challenges in terms of immune-related adverse events of ICIs. This review provides a valuable perspective for developing next-generation immunotherapies and optimizing personalized treatment strategies.