Background/Objectives: Breast cancer is a biologically complex malignancy whose high prevalence and therapeutic resistance represent a continuous challenge for global health. The Tumor Microenvironment (TME) is a crucial component in disease progression, and the Extracellular Matrix (ECM), particularly its 3D collagen architecture, is recognized for mediating interactions that influence invasion, metastasis, and pharmacological response. This review aims to critically synthesize recent evidence to elucidate the multifaceted role of collagen in the progression and modulation of therapeutic response in breast adenocarcinoma. Methods: A comprehensive literature review was conducted, analyzing studies addressing specific collagen subtypes, ECM stiffening (fibrosis), biomechanical signaling, and their impact on drug transport kinetics and immunomodulatory effects. Results: The results demonstrate that structural alterations of collagen not only orchestrate a pro-tumoral microenvironment, fostering aggressive phenotypes and immune evasion, but also create a physical barrier that compromises drug delivery efficiency and promotes metastatic dissemination. The synthesis of the data reinforces collagen as a potent prognostic biomarker and a promising therapeutic target for overcoming stroma-mediated resistance. Conclusions: Targeting the collagen-rich stroma and its 3D network is a critical frontier for therapeutic innovation. Developing adjuvant strategies to modulate the ECM has the potential to enhance clinical outcomes and optimize the distribution of antineoplastic agents, especially in patients with high degrees of tumor fibrosis.
Hirata et al. (2026) studied this question.