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). However, the frequent dysregulation of the CDK4/6-RB pathway and the inherently complex TIME in digestive cancers often precipitate primary and acquired drug resistance, which restricts their clinical efficacy. Consequently, elucidating the mechanisms that modulate drug sensitivity and developing biomarker-driven combination regimens have become critical research priorities. This review systematically summarizes the mechanisms governing the sensitivity of digestive tract tumors to CDK4/6 inhibitors. From the perspective of laboratory medicine, we further emphasize the importance of biomarker detection, therapeutic target assessment, and precision molecular subtyping in identifying patients most likely to benefit from CDK4/6 inhibitor-based therapies. In addition, we discuss the role of these agents in remodeling the TIME, evaluate current combination strategies aimed at overcoming resistance, and highlight future directions for advancing this rapidly evolving field.