TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment

SIMPLE SUMMARY: Metabolic reprogramming is an emerging hallmark in cancer. Beside the malignant compartment, the tumor microenvironment also undergoes to a metabolic skewing, contributing to the neoplastic progression and metastasizing process. Growing evidence pointed out a central role for Transforming Growth Factor Beta (TGF-β) as a driver of these metabolic changes in multiple cellular targets in cancer. This review deals with very recent discoveries on TGF-β-mediated metabolic reprogramming of stromal and immune cell population within the tumor microenvironment. In particular, we scrutinized current literature to highlight relevant metabolic checkpoints in the TGF-β cascade that sustain tolerogenic programs in tumors. ABSTRACT: Overcoming tumor immunosuppression still represents one ambitious achievement for cancer immunotherapy. Of note, the cytokine TGF-β contributes to immune evasion in multiple cancer types, by feeding the establishment of a tolerogenic environment in the host. Indeed, it fosters the expansion and accumulation of immunosuppressive regulatory cell populations within the tumor microenvironment (TME), where it also activates resident stromal cells and enhances angiogenesis programs. More recently, TGF-β has also turned out as a key metabolic adjuster in tumors orchestrating metabolic pathways in the TME. In this review, we will scrutinize TGF-β-mediated immune and stromal cell crosstalk within the TME, with a primary focus on metabolic programs.