The bidirectional interplay between T cell-based immunotherapies and the tumor microenvironment

Abstract T cell–based therapies, including Tumor Infiltrating Lymphocyte Therapy (TIL), T cell receptor engineered T cells (TCR T), and Chimeric Antigen Receptor T cells (CAR T), are powerful therapeutic approaches for cancer treatment. While these therapies are primarily known for their direct cytotoxic effects on cancer cells, accumulating evidence indicates that they also influence the tumor microenvironment (TME), by altering the cytokine milieu and recruiting additional effector populations to help orchestrate the antitumor immune response. Conversely, the TME itself can modulate the behaviour of these therapies within the host by either supporting or inhibiting their activity. In this review we provide an overview of clinical and preclinical data on the bidirectional influences between T cell therapies and the TME. Unravelling the interactions between T cell-based therapies and the TME is critical for a better understanding of their mechanisms of action, resistance, and toxicity, with the goal of optimizing efficacy and safety.