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Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor. These complex interactions require more sophisticated approaches for cancer therapy, and, therefore, advancing knowledge about dominant drivers of cancer within the TME is critical for designing therapeutic schemes. This review will provide knowledge about TME architecture, multiple signaling, and cross communications between cells within this milieu, and its targeting for immunotherapy of cancer. Cross‐talks between various cells in the stroma of tumor microenvironment (TME) in favor of or against of tumor progression. Release of a variety of proteins, transcription factors, cytokines, chemokines, and so forth from cells inside the TME direct the fate of cancer. Concentration of these TME components along with temperature, circadian rhythm, and pH inside this microenvironment determine the fate of signaling. Complexity of the TME is a reason for failure of most of the conventional therapies against cancer. [ABSTRACT FROM AUTHOR]