Effective immunotherapy requires thorough knowledge of the tumour microenvironment. Indeed, the interplay among the immune system, the tumour and treatment is conditioned by the composition of the tumour microenvironment. In addition, it must be taken into account that homeostasis of the tumour microenvironment is highly dynamic and changes rapidly in function of many factors, such as inflammation, hypoxia, tumour volume, all of which change over time, and the effect of treatments. All these elements interact with each other and with conditions related to the tumour (i.e. mutational load, rate of clonal and subclonal mutations) and to host (life style, diet, obesity, age). All these factors as well as their interplay, affect the response to immunotherapy. The target of this short review is to summarise some of the major aspects that impact the homeostasis of the tumour microenvironment and how its structure can drive treatment choice.