Cancer is more than just a collection of tumor cells. The complex tumor system, including the tumor immune microenvironment (TIME), is continually changing. Tumor cells are in constant communication with all stromal elements (e.g., fibroblasts, endothelial cells, and extracellular matrix) and immune effector cells (e.g., T cells, B cells, natural killer cells, dendritic cells, macrophages, and myeloid-derived suppressor cells). Together, these intricate interactions among cell and molecular signaling pathways collectively drive tumor growth, tumor invasion, and metastasis and significantly affect the efficacy of cancer treatments. Recent investigations, from a tumor-centric research paradigm to a complete evaluation of the local tumor microenvironment, have revealed the importance of the TIME. Although reviews in these fields typically focus on cellular/molecular breakdowns of the TIME and evasion of the immune system, a systematic study of its dynamic evolution is lacking. This review comprehensively discusses the major regulators and networks involved in the dynamic evolution of the TIME, the spatiotemporal dynamics of TIME components, metabolic reprogramming as an engine of TIME evolution, the targeting of metabolic regulators, and niches for TIME modulation, clinical and translational challenges, and future prospects. This information could help researchers explore the TIME and generate new therapeutic strategies.
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