What question did this study set out to answer?

To explore how the tumor microenvironment influences the therapy response in HER2-low breast cancer.

March 29, 2026Pharmaceuticals1 citationsOpen Access

Mechanisms of Resistance and Synergy: The Role of Tumor Microenvironment in HER2-Low Breast Cancer Therapy

YBYoussef BasemMisr University for Science and Technology AAAlamer AtaMisr University for Science and Technology ASAbanoub SherifMisr University for Science and Technology

Key Points

To explore how the tumor microenvironment influences the therapy response in HER2-low breast cancer.
Review current literature on HER2-low breast cancer
Examine the role of the tumor microenvironment in ADC efficacy
Analyze resistance mechanisms in HER2-low tumors
HER2-low breast cancer shows variable responses to antibody-drug conjugates
The tumor microenvironment contributes to resistance against ADCs
Effective payload delivery is often hindered by the tumor microenvironment

Abstract

HER2-low breast cancer, also known as IHC 1+ or IHC 2+ without ERBB2 amplification, is a new concept in the biology of breast cancer that has removed the binary classification of HER2-positive or HER2-negative breast cancer. The recent introduction of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), has improved therapeutic outcomes for HER2-low breast cancer by demonstrating high efficacy in HER2-low tumors through efficient payload delivery. However, differences in ADC efficacy exist among HER2-low breast cancer patients, with tumor cells showing resistance to ADCs. Recent research indicates that the tumor microenvironment (TME) plays a critical role in determining the efficacy of ADCs against tumor cells. TME creates a barrier to the delivery of ADCs to tumor cells that show resistance to ADCs. This review article aims to highlight the current understanding of the biology of HER2-low breast cancer and its response to ADCs with reference to the tumor microenvironment.

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