Thymosin α-1 in Cancer Therapy: Immunomodulatory Mechanisms, Clinical Applications, and Translational Perspectives.

Cancer remains a leading cause of global mortality, underscoring the need for therapeutic strategies that not only target tumor cells but also enhance antitumor immunity. Thymosin α-1 (Tα1), a naturally occurring thymic peptide, has emerged as a promising immunomodulatory agent with potential applications in cancer therapy. Tα1 regulates both adaptive and innate immune responses by promoting T-cell maturation and T helper cell type 1 (Th1) polarization, enhancing natural killer cell activity, modulating dendritic cell function, and influencing tumor-associated macrophages and myeloid-derived suppressor cells. Through these actions, Tα1 may contribute to immune surveillance and modulation of the tumor microenvironment. Preclinical and clinical studies suggested that Tα1 may possess antitumor activity and could enhance the efficacy of conventional and emerging cancer therapies, including chemotherapy, radiotherapy, and immune checkpoint inhibitors. Emerging evidence also indicates that Tα1 may improve immune infiltration in immunologically "cold" tumors and help mitigate certain immune-related adverse events associated with immunotherapy. Clinical investigations in malignancies, such as non-small cell lung cancer, hepatocellular carcinoma, and metastatic melanoma, have reported a favorable safety profile and potential therapeutic benefits, although the available evidence remains limited and heterogeneous. This review summarizes the biological functions, immunoregulatory mechanisms, and therapeutic potential of Tα1 in oncology. We discuss recent advances in Tα1-based combination strategies, clinical observations, translational opportunities, and current limitations of the evidence. Furthermore, key challenges and future research directions are highlighted to provide an updated perspective on the role of Tα1 as a potential adjunctive immunomodulatory agent in modern cancer immunotherapy.