Advancing triple-negative breast cancer therapy: 3D in vitro models to unravel drug resistance mechanisms and tumor microenvironment interactions

Abstract

Triple-negative breast cancer (TNBC) poses considerable clinical challenges due to its aggressive nature, early metastasis, and limited treatment options. The simplified 2D models and the physiological differences in animal models often result in inconsistent responses to anticancer drugs. To tackle these challenges, three-dimensional (3D) in vitro bioengineered models that accurately replicate the in vivo tumor microenvironment (TME) have been developed, offering a more reliable platform for preclinical drug testing. Recent advancements in cell culture techniques have facilitated the creation of 3D models derived from patient tissues and tumors, which effectively mimic the native tissue environment and exhibit drug sensitivity and cytotoxicity behaviors similar to those observed in vivo. It is increasingly acknowledged that the extracellular matrix and cellular diversity within the TME significantly influence the fate of cancer cells. Consequently, strategies to explore drug resistance mechanisms must account for both microenvironmental factors and genetic mutations. This review examines 3D in vitro model systems that integrate microenvironmental influences to investigate drug resistance mechanisms in breast cancer. We discussed various bioengineered models, including spheroid-based, biomaterial-based (such as polymeric scaffolds and hydrogels), patient-derived xenograft (PDX), 3D bioprinting, and microfluidic chip-based models. Additionally, we discuss the relevance of these 3D models in understanding the effects of TME signals on drug response and resistance, as well as their potential for developing strategies to overcome drug resistance and optimize treatment regimens.