Objective:

To summarize the mechanisms governing the sensitivity of gastrointestinal tumors to CDK4/6 inhibitors and discuss the role of these agents in remodeling the tumor immune microenvironment, emphasizing the urgent need to address resistance mechanisms.

Key Findings:

• CDK4/6 inhibitors can remodel the tumor immune microenvironment by enhancing antigen presentation and promoting effector T cell infiltration.
• Resistance to CDK4/6 inhibitors in GI cancers is often due to dysregulation of the CDK4/6-RB pathway and complex tumor microenvironments, including alternative cell cycle regulatory networks.
• Combination therapies involving CDK4/6 inhibitors with immune checkpoint inhibitors and other agents may enhance drug sensitivity and delay resistance.

Interpretation:

The review highlights the potential of CDK4/6 inhibitors in GI cancers while acknowledging the challenges posed by resistance mechanisms and the need for biomarker-driven approaches.

Limitations:

• The development of CDK4/6 inhibitors in GI cancers has been slower compared to breast cancer, which may limit treatment options.
• GI cancers exhibit significant heterogeneity, complicating the application of CDK4/6 inhibitors and necessitating personalized treatment approaches.

Conclusion:

Understanding the mechanisms of resistance and developing combination therapies are critical for improving the efficacy of CDK4/6 inhibitors in gastrointestinal malignancies.