Cancer develops in a complex and dynamic TME, which exerts profound impacts to disease progression. Cancer cells are in close relationship with diverse non-cancer cell types within the TME, forming a functional nexus that facilitates tumor initiation, survival, and exacerbation. Cytotoxicity generated by treatments including chemotherapy, radiation, and targeted therapy eliminates many malignant cells within the cancer cell population; however, surviving cells are frequently retained in specific TME niches. Such protection minimizes the sensitivity to anti-cancer agents and generates resistant subclones through distinct mechanisms, prominently through acquired resistance conferred by a large body of soluble factors released from damaged or remodeled stroma. Alternatively, BMDCs, including MSCs and Tregs, mediate immunomodulation and prevent inflammation by restraining the activity of cytotoxic T cells, correlating with poor prognosis. Either acquired resistance or immunosurveillance evasion promotes cancer cell survival and subsequent expansion, allowing development of more advanced phenotypes, including tumor relapse, distant metastasis, and therapeutic failure, eventually causing high mortality in clinical settings. CAF, Carcinoma-associated fibroblast; MSC, Mesenchymal stem cell; BMDC, Bone marrow-derived cell; Treg cell, Regulatory T cell; EC, Endothelial cell; ECM, Extracellular matrix; TAM, Tumor-associated macrophage.