The radiobiology of TGFβ

Ionizing radiation is a pillar of cancer therapy that is deployed in more than half of all malignancies. The therapeutic effect of radiation is attributed to induction of DNA damage that kills cancers cells, but radiation also affects signaling that alters the composition of the tumor microenvironment by activating transforming growth factor beta (TGF beta). TGF beta is a ubiquitously expressed cytokine that acts as biological lynchpin to orchestrate phe-notypes, the stroma, and immunity in normal tissue; these activities are subverted in cancer to promote ma-lignancy, a permissive tumor microenvironment and immune evasion. The radiobiology of TGF beta unites targets at the forefront of oncology-the DNA damage response and immunotherapy. The cancer cell intrinsic and extrinsic network of TGF beta responses in the irradiated tumor form a barrier to both genotoxic treatments and immuno-therapy response. Here, we focus on the mechanisms by which radiation induces TGF beta activation, how TGF beta regulates DNA repair, and the dynamic regulation of the tumor immune microenvironment that together oppose effective cancer therapy. Strategies to inhibit TGF beta exploit fundamental radiobiology that may be the missing link to deploying TGF beta inhibitors for optimal patient benefit from cancer treatment.