Tumor Microenvironment Heterogeneity: A Review of the Biology Masterpiece, Evaluation Systems, and Therapeutic Implications

A tumor can be considered as a highly heterogeneous functional tissue, connected and dependent on the microenvironment, which sends and receives signals to and from the tumor tissue itself. Tumor cells alter the mechanical properties of the microenvironment in order to create favorable conditions for their proliferation. Stromal cells and non‐cellular elements of the extracellular matrix (ECM), including the host immune system, the fibrous scaffolding, the fundamental substance, and blood vascularization can determine tumoral cell morphologies, functions, aggressiveness, and response to treatment, as well as an accurate assessment of prognosis of the patients. Robust morphometric digital pathology techniques that are able to standardize measurements and analyse whole sets of immunohistochemical images are called for to identify, describe, and quantify the elements of the ECM. The computer‐automated segmentation algorithms are therefore required to increase the knowledge on the tumor microenvironment heterogeneity and to provide new therapeutic targets.