New Insights into How Cancer Cells Develop Resistance to CDK4/6 Inhibitors

Recent research has shed light on a significant challenge in cancer treatment: the ability of cancer cells to create a protective microenvironment that hinders the effectiveness of CDK4/6 inhibitors. These targeted drugs have been instrumental in improving outcomes for patients with advanced HR+/HER2- breast cancer, often used alongside hormonal therapy. Despite their success, many patients experience relapse due to resistance mechanisms within tumors.

A groundbreaking study published in Nature Cancer reveals that some tumors adapt to CDK4/6 inhibition by fostering an immunosuppressive environment. This microenvironment comprises cells such as gamma delta T-cells and macrophages that promote tumor growth and suppress immune responses. Notably, the tumor’s response includes elevating these immune-modulating cells, which contribute to therapy resistance.

The researchers found that radiation therapy can prevent the formation of this immunosuppressive microenvironment by blocking key signaling pathways responsible for increasing gamma delta T-cells and macrophages. In mouse models, combining radiation with CDK4/6 inhibitors and hormonal therapy proved more effective than standard treatment alone.

Moreover, the study suggests that targeting gamma delta T-cells and immunosuppressive macrophages with existing drugs presents an alternative for patients who cannot undergo radiation therapy. Blood and tissue samples from human patients confirmed that high levels of gamma delta T-cells correlated with faster cancer relapse, indicating their potential as predictive markers.

Looking ahead, the research team plans to evaluate combined therapies—using CDK4/6 inhibitors with agents that target these immune cells—in clinical trials involving breast cancer patients. The goal is to improve responses and prevent resistance by modulating the tumor microenvironment more effectively.

This study highlights the importance of understanding tumor-immune interactions in developing more durable cancer treatments and underscores new therapeutic strategies to overcome resistance to CDK4/6 inhibitors.

Source: https://medicalxpress.com/news/2025-07-cancer-cells-microenvironment-cdk46-inhibitors.html