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.