Recent years have seen the emergence of novel cancer immunotherapies such as those relying on genetically engineered T cells. Although CAR T cells can be extremely effective in killing malignant B cells, this strategy has not yet produced favorable clinical responses in targeting solid malignancies. Over the last years, we have improved our understanding of key negative and positive regulations of anti-tumoral immune cells that directly apply to CAR T cells. In particular, we have shown that T lymphocytes may be blocked in their antitumor activities and identified a detrimental impact of extracellular matrix and of macrophages associated with progressing tumors (TAM) (Salmon, J. Clin. Invest. 2012) (http://www.ncbi.nlm.nih.gov/pubmed/22293174), (Peranzoni, PNAS 2018) (http://www.ncbi.nlm.nih.gov/pubmed/29632196). Our overall objective is to take advantage of tools and expertise developed by the laboratory to target these cells and elements, in order to overcome them and generate CAR T cells with an improved efficacy against solid tumors.