Figure 1.

Factors involved in breast cancer recurrence. The left side of the picture shows the histopathologic types and molecular subtypes of the tumors in the recurrence of the disease. The right side of the picture shows the role of tumor heterogeneity, microenvironment, and immune system in breast cancer recurrence. Several clonal tumors containing CSCs are seen in tumor bulk and CSCs can affect the heterogenic migration of various clones in a single tumor. CSC also promote the EMT process and cause metastasis of BC tumor cell to the cervix, brain, liver, lung, and bone marrow. Cancer cells can recruit the immune system to progress tumor or even metastasis. Specific immune cells, including macrophages, lymphocytes, NK cells, dendritic cells (DCs), and neutrophils, are abundant and actively involved in the progression or suppression of cancer dissemination at the site of metastasis. Indeed, cancer cells can indirectly modulate and suppress the immune response (30, 32). CAFs promote tumor progression by initiating extracellular matrix remodeling through cytokine secretion. CAFs could suppress or avoid the immune response by promoting the recruitment of regulatory T cells (Treg), which is mediated by inflammation, or stopping the proliferation of T helper cells and killer T cells (28, 29). Work as tumor-modifying cells that may induce a change in cancer cell phenotype. CAAs produce hormones, growth factors, and cytokines. TAMs are the predominant immune cell types with immunosuppressive M2 polarized phenotypes that secrete tumor cytokines. Exosomes are essential in impairing both the adaptive and innate immune systems. It was shown that exosomal PDL1 derived from BC promotes and protects tumor growth by attaching to the PD-1 receptor of the CD8 T cells; thus, their adaptive killing activities are inhibited. Moreover, T-cells inhibit exosome secretion significantly through their anti-tumor immunity. In addition, uncontrolled cell proliferation induced by exosomes leads to inadequate nutrient and oxygen flow that derives the tumor microenvironment from becoming hypoxic. This process further triggers Epithelial-to-Mesenchymal Transition (EMT) and also promotes a more invasive phenotype. Further explanations are available in the text. TAN, tumor-associated neutrophil; TAM, tumor-associated macrophage; CAA, cancer-associated adipocyte; CAF, cancer-associated fibroblast; ECM, extracellular matrix; EMT, epithelial to mesenchymal transition; TNBC, triple-negative breast cancer; CSC, cancer stem cell. The figure was created using Biorender (https://biorender.com).