Tumor microenvironment in breast cancer: cellular crosstalk, pathways, and therapeutic insights

Breast cancer is the leading cancer type that is reported in women worldwide, with its 2.3 million annual incidence and 685,000-related deaths (WHO, 2023). Although genetic mutations have proven to be major driving agents of tumorigenesis, the tumor microenvironment (TME) is increasingly being considered as the definitive indicator of disease progression, metastasis, immune evasion and therapeutic resistance. It is an active, diverse cellular webwork of substances cancer-related fibroblasts, (CAFs), tumor-related macrophages, (TAMs), regulatory T cells, (Tregs), myeloid-derived suppressor cells (MDSCs), and cancer-related adipocytes; (CAAs). These cellular processes interact reciprocally with not only malignant cells through paracrine communication but also through the composition of the extracellular matrix, (ECM). Recent research indicates that CAFs produce pro-invasive factors i.e. TGF-B and HGF whereas TAMs tend to be M2-like and secret VEGF and IL-10 to encourage angiogenesis and immune subversion. Cytokines, chemokines, ECM proteins, and tumor-derived EVs are non-cellular factors serving to alter cellular phenotypes and facilitate construction of metastatic niche. Besides oncogenic microRNAs (e.g., miR-21, miR-10b) that is released in exosome, hypoxia-mediated activation of HIF-1a induces both neovascularization and metabolic reprogramming. The repolarization of TAM (e.g. CSF1R inhibitors) and depletion of CAF and inhibition of EV pathway are also being explored as therapeutic mechanisms against TME resistance and are in preclinical and clinical development. In particular, the combination procedures with immunomodulation and TME disruption have demonstrated some success in conquering resistance in TNBC models. Therefore, it is paramount to understand how the surrounding tissue, the immune system, the immune system, and other elements behave over time and space as cofounding partners of tumors, in a way that would create better precision and clinical outcomes in breast cancer patients.