Activin A-Targeted Therapy in Cancer: An Updated Review on Challenges and Opportunities in Clinical Translation.

Activin A (ActA) is a cytokine from the TGF-β superfamily that mediates a vast number of physiological mechanisms, mainly through the SMAD signaling pathway. Growing evidence indicates that ActA overexpression is also correlated with poor prognosis in cancer patients and several tumor characteristics, including cancer proliferation, metastasis, immunosuppression, drug resistance, cachexia, and cancer-associated fibroblast activation. As such, ActA-targeted therapy has been viewed as a potential adjuvant therapy alongside other anti-cancer modalities that may result in more efficient anti-cancer effects, such as stronger immune responses, overcoming drug resistance, reversing cachexia, etc. However, despite its interesting concept, targeting ActA is not without certain challenges and considerations. Indeed, ActA has unexpectedly shown anti-tumor effects in some cases, which might be explained by differences in the expression levels of different ActA receptors on the cell surface, activation of non-SMAD pathways, and imbalance in ActA levels. Besides, many of the current ActA antagonists lack enough specificity and, as a result, bind to non-ActA receptors as well. Furthermore, ubiquitous expression of ActA in the body can cause serious adverse effects following systemic administration. Furthermore, to address these issues, anti-ActA monoclonal antibodies and nanoparticle drug delivery systems have recently been suggested to target ActA with better precision in the affected area. In this review, first, we provide the different implications of ActA in cancer. Then, we discuss the recent insights into targeting ActA signaling as an adjuvant therapy alongside other anti-cancer modalities, as well as the possible challenges and novel opportunities on the path of clinical translation.