IL-15 Plus Thymosin α1 Reduces Senescent Hepatic CD8<sup>+</sup> T Cells in Hepatocellular Carcinoma via PI3K/AKT Suppression.
This preclinical study investigated whether combining interleukin-15 (IL-15) with thymosin alpha 1 (Tα1) could reverse CD8+ T cell immunosenescence and enhance antitumor immunity in hepatocellular carcinoma (HCC). Using an orthotopic HCC model in aged C57BL/6 mice (22–26 months old), animals were randomized to saline, IL-15 alone, Tα1 alone, or combination therapy. The study found that the combination treatment significantly suppressed tumor growth and prolonged survival compared to either agent alone or control. Mechanistically, combination therapy reduced the proportion of senescent CD8+ T cells, expanded activated effector populations, and upregulated cytotoxic markers such as granzyme B, perforin, and interferon-gamma. Transcriptomic and Western blot analyses indicated that the combination suppressed chronically overactivated PI3K/AKT signaling in hepatic CD8+ T cells — an effect confirmed by in vitro experiments using primary human CD8+ T cells co-cultured with Huh7 hepatoma cells, where the AKT agonist SC79 reversed the therapeutic benefit. Key limitations include the exclusively preclinical design (no human clinical data), use of a single mouse HCC model, and the need for further validation of the proposed mechanism in clinical settings.