Cell-based immunotherapy, for example, chimeric antigen receptor T (CAR-T) cell immunotherapy, has revolutionized cancer treatment, particularly for blood cancers. However, factors such as insufficient T cell tracking, tumour heterogeneity, inhibitory tumour microenvironment (TME) and T cell exhaustion limit the broad application of CAR-based immunotherapy for solid tumours. In particular, the TME is a complex and evolving entity, which is composed of cells of different types (e.g., cancer cells, immune cells and stromal cells), vasculature, soluble factors and extracellular matrix (ECM), with each component playing a critical role in CAR-T immunotherapy. Thus, developing approaches to mitigate the inhibitory TME factors is critical for future success in applying CAR-T cells for solid tumour treatment. Accordingly, understanding the bilateral interaction of CAR-T cells with the TME is in pressing need to pave the way for more efficient therapeutics. In the following review, we will discuss TME-associated aspects with an emphasis on T cell trafficking, ECM barriers, abnormal vasculature, solid tumour heterogenicity and immune suppressive microenvironment. We will then summarize current engineering strategies to overcome the challenges posed by the TME-associated factors. Lastly, the future directions for engineering efficient CAR-T cells for solid tumour therapy will be discussed.
