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 physiologicalmechanisms, mainly through the SMAD signaling pathway. Growing evidence indicates that ActAoverexpression is also correlated with poor prognosis in cancer patients and several tumor characteristics, includingcancer proliferation, metastasis, immunosuppression, drug resistance, cachexia, and cancer-associatedfibroblast activation. As such, ActA-targeted therapy has been viewed as a potential adjuvant therapy alongsideother anti-cancer modalities that may result in more efficient anti-cancer effects, such as stronger immuneresponses, overcoming drug resistance, reversing cachexia, etc. However, despite its interesting concept, targetingActA is not without certain challenges and considerations. Indeed, ActA has unexpectedly shown anti-tumoreffects in some cases, which might be explained by differences in the expression levels of different ActAreceptors on the cell surface, activation of non-SMAD pathways, and imbalance in ActA levels. Besides, manyof 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 systemicadministration. Furthermore, to address these issues, anti-ActA monoclonal antibodies and nanoparticle drugdelivery systems have recently been suggested to target ActA with better precision in the affected area. In thisreview, first, we provide the different implications of ActA in cancer. Then, we discuss the recent insights intotargeting ActA signaling as an adjuvant therapy alongside other anti-cancer modalities, as well as the possiblechallenges and novel opportunities on the path of clinical translation.