Regulation of Immune Checkpoints: From Molecular Mechanisms to Clinical Therapies

ABSTRACT Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by targeting crucial coinhibitory pathways. Pathways involving PD‐1/PD‐L1 and CTLA‐4 are essential for immune homeostasis but are frequently exploited by tumors to evade immune surveillance. ICIs block these interactions, unleashing a potent antitumor immune response. However, broad clinical efficacy is limited by low response rates, immune‐related adverse events, and the pervasive challenge of primary or acquired resistance. This review summarizes the fundamental molecular mechanisms of key checkpoints (PD‐1/PD‐L1, CTLA‐4, TIM‐3) and highlights recent clinical progress in ICI monotherapies and combination strategies. We systematically explore multifaceted mechanisms of resistance, encompassing both tumor‐intrinsic and extrinsic factors. Furthermore, we outline novel therapeutic approaches being designed to overcome this resistance. Finally, we discuss promising predictive biomarkers and precision immuno‐oncology strategies. This review provides a critical framework for navigating the current landscape and offers a rationale to guide the future development of effective combination therapies to improve patient outcomes.