CDK4/6-targeted therapy for gastrointestinal cancers: from resistance mechanisms to immuno-combination strategies guided by biomarkers

Gastrointestinal (GI) cancers, encompassing esophageal, gastric, colorectal, hepatocellular, and pancreatic cancers, represent a major global health burden with persistently high morbidity and mortality. Given the limited therapeutic options and poor prognoses for patients with advanced-stage disease, there is an urgent and unmet clinical need for novel targeted therapies.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (such as palbociclib, ribociclib, and abemaciclib) exert their effects by arresting the cell cycle at the G1/S checkpoint. Their landmark clinical success in hormone receptor-positive breast cancer has highlighted the therapeutic potential of targeting cell cycle regulation, thereby prompting extensive investigation into their application in solid tumors of the digestive system.

Emerging evidence indicates that, beyond their direct antiproliferative effects, CDK4/6 inhibitors profoundly remodel the tumor immune microenvironment (TIME). By enhancing tumor antigen presentation, diminishing the immunosuppressive activity of regulatory T cells (Tregs), and promoting effector T cell infiltration, these agents provide a robust mechanistic rationale for synergistic combinations with immune checkpoint inhibitors (ICIs).