Targeting tumor fibrosis: a new paradigm for overcoming resistance to breast cancer treatment

Over the past decade, advancements in oncology have elucidated the critical role of the tumor microenvironment in cancer progression. Within this framework, fibrotic foci, resulting from aberrant deposition and structural remodeling of the extracellular matrix, have been identified as a fundamental pathological characteristic intimately associated with breast cancer invasion, immune evasion, and therapeutic resistance. This review systematically elucidates the multi-step formation process of fibrotic foci and delineates their precise regulation by various signaling networks, including the TGF-β pathway, the autotaxin-lysophosphatidic acid axis, hypoxia, and metabolic reprogramming. Beyond these canonical pathways, emerging evidence underscores the pivotal contributions of non-coding RNAs and cellular senescence, especially the senescence of cancer-associated fibroblasts, in sustaining and amplifying the fibrotic niche. The resulting fibrotic microenvironment establishes physical and biochemical barriers that significantly impede drug penetration and suppress immune cell function, contributing to the failure of chemotherapy, radiotherapy, and immunotherapy. Advancements in diagnostic techniques, such as radiomics, artificial intelligence, and molecular markers, are enhancing the precise assessment of fibrotic foci. Therapeutically, emerging strategies include targeting extracellular matrix remodeling, key signaling pathways, modulating the immune microenvironment, as well as employing nanotechnology and physical therapies. A structured overview of both preclinical strategies and ongoing or completed clinical trials in this domain is provided, highlighting the translational landscape of anti-fibrotic interventions. These multi-dimensional intervention strategies show potential for overcoming current treatment bottlenecks in breast cancer, thereby paving the way for novel approaches to enhance patient prognosis.