Molecular Pathways and Mechanisms of TGFb in Cancer Therapy

Even though the number of agents that inhibit TGFI3 being tested in patients with cancer has grown substantially, clinical benefit from TGFI3 inhibition has not yet been achieved. The myriad mechanisms in which TGFI3 is protumorigenic may be a key obstacle to its effective deployment; cancer cells frequently employ TGFI3-regulated programs that engender plasticity, enable a permissive tumor microenvironment, and profoundly suppress immune recognition, which is the target of most current early-phase trials of TGFI3 inhibitors. Here we discuss the implications of a less well-recognized aspect of TGFI3 biology regulating DNA repair that mediates responses to radiation and chemotherapy. In cancers that are TGFI3 signaling competent, TGFI3 promotes effective DNA repair and suppresses error-prone repair, thus conferring resistance to genotoxic therapies and limiting tumor control. Cancers in which TGFI3 signaling is intrinsically compromised are more responsive to standard gen- otoxic therapy. Recognition that TGFI3 is a key moderator of both DNA repair and immunosuppression might be used to synergize combinations of genotoxic therapy and immunotherapy to ben- efit patients with cancer.