Pharmacologic doses of ascorbic acid and seleno-L-methionine are new and novel class of transforming growth factor-beta 1 inhibitor: mechanisms and therapeutic potential

TGF-?1, a multifunctional cytokine ubiquitously overexpressed in advanced cancers, is a critical target implicated in drug resistance, immune evasion, increased tumor angiogenesis, and unstable TME. We discovered for the first time that pharmacologic doses of SLM and AA are potent in vivo selective inhibitors of TGF-?1. Inhibition of TGF-?1 was associated with time-dependent inhibition of HIFs, PD-L1, VEGF, CAR-T cell activation, activation of TET by AA, inhibition of DNMTs by SLM, stabilization of tumor vasculature, increased drug delivery to tumor cells, and enhanced efficacy of oncolytic agents. The pleiotropic effects induced by pharmacologic doses and schedule of SLM offer the potential for enhancing the therapeutic efficacy of immunotherapy in cancer patients.