Targeting transforming growth factor-beta signaling for enhanced cancer chemotherapy

During the past decades, drugs targeting transforming growth factor-beta (TGF beta) signaling have received tremendous attention for late-stage cancer treatment since TGF beta signaling has been recognized as a prime driver for tumor progression and metastasis. Nonetheless, in healthy and pre-malignant tissues, TGF beta functions as a potent tumor suppressor. Furthermore, TGF beta signaling plays a key role in normal development and homeostasis by regulating cell proliferation, differentiation, migration, apoptosis, and immune evasion, and by suppressing tumor-associated inflammation. Therefore, targeting TGF beta signaling for cancer therapy is challenging. Recently, we and others showed that blocking TGF beta signaling increased chemotherapy efficacy, particularly for nanomedicines. In this review, we briefly introduce the TGF beta signaling pathway, and the multifaceted functions of TGF beta signaling in cancer, including regulating the tumor microenvironment (TME) and the behavior of cancer cells. We also summarize TGF beta targeting agents. Then, we highlight TGF beta inhibition strategies to restore the extracellular matrix (ECM), regulate the tumor vasculature, reverse epithelial-mesenchymal transition (EMT), and impair the stemness of cancer stem-like cells (CSCs) to enhance cancer chemotherapy efficacy. Finally, the current challenges and future opportunities in targeting TGF beta signaling for cancer therapy are discussed.