Research & Bioactivity
Thymosin Alpha 1 is a naturally occurring peptide originally isolated from thymic tissue, and researchers have studied it extensively in relation to immune system regulation and T cell biology. Much of the published research has examined its role in modulating immune responses, particularly in the context of conditions involving immune dysfunction or suppression, with studies conducted in both human clinical trials and in vitro cell culture models. Researchers have investigated how Thymosin Alpha 1 influences T cell populations, including its potential to support thymic activity and affect the behavior of CD8 T cells, with some studies exploring mechanisms involving signaling pathways such as PI3K/AKT. Clinical research has also examined Thymosin Alpha 1 in combination with immune checkpoint inhibitors in oncology settings, including studies in non-small cell lung cancer and gastric cancer, where investigators assessed immune function markers alongside standard efficacy and safety endpoints. Additional research has explored its relationship with viral reservoirs in HIV models and its effects on immune homeostasis in liver disease contexts, including studies involving dendritic cells and cytokine interactions such as the IL-15 pathway. Across these research areas, studies have generally focused on understanding how this peptide interacts with immune cell populations and signaling networks under various experimental and clinical conditions.
Published Research
Thymalfasin combined with immune checkpoint inhibitors in the treatment of non-small cell lung cancer: A retrospective study on efficacy, safety, and immunological function.
Wang P, Zhang X, Xiang C, Li G, Zhang Y — 2026
OBJECTIVES: To evaluate the efficacy, safety, and immunomodulatory effects of thymalfasin in combination with different immune checkpoint inhibitor (ICI)-based regimens in patients with advanced driver gene-negative non-small cell lung cancer(NSCLC). METHODOLOGY: A retrospective analysis was conducted on 120 patients with advanced NSCLC treated at Shijiazhuang People's Hospital between January 2021 to December 2024. Patients were assigned to three groups: Group-A( 42), platinum-based doublet chemotherapy + ICIs + thymalfasin; Group-B( 44), single-agent chemotherapy + ICIs + thymalfasin; Group-C( 34), ICIs + thymalfasin. Assessed objective response rate(ORR), disease control rate(DCR), progression-free survival(PFS), overall survival (OS), adverse events(AEs), immunological indices, and quality of life score and 6-min walk distance [6MWD]). RESULTS: ORR and DCR did not differ significantly among groups( 0.05, respectively). Median PFS and OS were significantly longer in chemotherapy-containing regimens(Groups-A and B) compared with Group-C(0.05, respectively), whereas no significant differences were observed between Groups-A and B. The incidence of AEs, including myelosuppression and gastrointestinal reactions, was comparable across groups(all 0.05). After treatment, all groups demonstrated significant improvements in immunological function(all 0.05), with Group-A showing the most pronounced increases in CD4, IgG, and IgA levels compared with Group-C ( 0.05, respectively). Improvements in FACT-L scores were most evident in Group-A ( 0.05), and declines in 6MWD were smallest in this group( 0.05). CONCLUSION: Thymalfasin combined with ICIs and chemotherapy, particularly platinum-based doublet regimens, may significantly prolong survival, enhance immune function, and improve quality of life in patients with advanced NSCLC, without increasing treatment-related toxicity.
Thymosin α1 improves the outcomes of patients with hepatitis B virus-related acute-on-chronic liver failure by restoring immune balance.
Li ZH, Wu LL, Zhu YQ, Hu ZX, Meng SB, et al. — 2026
BACKGROUND: Thymosin α1 (Tα1) has been shown to improve survival in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), but its immunomodulatory mechanisms remain unclear. This study investigated how Tα1 restores immune homeostasis to confer a survival benefit in these patients. METHODS: In this open-label, randomized controlled trial (NCT03082885), 73 patients with HBV-ACLF received either standard medical therapy (SMT, n = 38) or SMT plus Tα1 (n = 35). Peripheral blood immune cell subsets were analyzed by flow cytometry and serum cytokine levels were measured by ELISA. Patients were stratified by 90-day transplant-free survival. RESULTS: Patients who survived at 90 days exhibited a higher proportion of effector T (TE) cells and lower levels of regulatory T cells (Tregs) at baseline compared to non-survivors. Survivors also had significantly higher initial levels of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and lower levels of TGF-β. Over time, survivors showed a gradual decline in inflammatory markers, whereas non-survivors developed a progressive inflammatory storm. Tα1 treatment significantly increased 90-day transplant-free survival and was associated with reduced frequencies of Tregs and CD226 Treg subsets at weeks 4-8. Tα1 also moderated the late-stage hyperinflammatory response without compromising early immune activation. CONCLUSIONS: Tα1 improves clinical outcomes in HBV-ACLF by rebalancing the immune response-mitigating excessive inflammation and preventing immune paralysis by modulating T-cell differentiation and cytokine production, thereby breaking the cycle of hyperinflammation and immunosuppression that characterizes ACLF progression.
IL-15 Plus Thymosin α1 Reduces Senescent Hepatic CD8 T Cells in Hepatocellular Carcinoma via PI3K/AKT Suppression.
Wu F, Guo Z, Guan J, Xu J, Chen Y, et al. — 2026
BACKGROUND AND AIM: CD8 T cell immunosenescence drives hepatocellular carcinoma (HCC) progression and impedes therapeutic efficacy. We hypothesized that combining interleukin-15 (IL-15), which rescues senescent CD8 T cells peripherally, with thymosin alpha 1 (Tα1), which replenishes the T cell pool via thymic rejuvenation, may synergistically overcome immunosenescence and enhance antitumor immunity in HCC. METHODS: An orthotopic HCC model was established in aged C57BL/6 mice (22-26 months), randomly assigned to receive saline, IL-15, Tα1, or combined therapy. Tumor progression was monitored by bioluminescence imaging, survival analysis, and histopathology. Hepatic CD8 T cell phenotype and function were evaluated by multicolor flow cytometry, immunofluorescence, transcriptomic sequencing, and Western blotting. In vitro validation used primary human CD8 T cells co-cultured with Huh7 hepatoma cells. RESULTS: The combination therapy significantly suppressed tumor growth and prolonged survival. It reduced the proportion of senescent CD8 T cells while expanding activated effector populations, enhanced proliferative capacity, and upregulated cytotoxic mediators including granzyme B, perforin, and interferon-gamma. Transcriptomic and protein-level analyses revealed that the combination attenuated chronically overactivated phosphatidylinositol 3-kinase/protein kinase B signaling in hepatic CD8 T cells. A protein kinase B agonist, SC79, abrogated these therapeutic effects in vitro, confirming pathway suppression as the key mechanism. CONCLUSIONS: Combined IL-15 and Tα1 therapy reverses CD8 T cell senescence and enhances antitumor immunity in HCC through suppression of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.
Thymosin α1-induced secretion of the IL-15/RA complex by THP-1-derived dendritic cells restrains HIV latency .
Chen C, Xun J, Wang J, Zhang R, Qi T, et al. — 2026
Viral reservoir presents a significant challenge in HIV-1 cure. We previously observed that Thymosin α1 (Tα1) may restrict the reservoir through the IL-15 pathway. However, the precise mechanism remains to be fully elucidated. Peripheral blood mononuclear cells (PBMCs) were obtained from people living with HIV-1 (PLWH). In vitro, THP-1 cells were differentiated into mature monocyte-derived dendritic cells (MoDCs) and co-cultured with PBMCs under various conditions. Intracellular HIV-1 p24 levels, CD8+ T and NK cell functionality, and reservoir size were evaluated. In vitro, Tα1 stimulation of MoDCs resulted in significant immune response and secretion of IL-15/RA complex ( < 0.001). This interaction with IL-2 Rβ/γ receptors on T cells enhanced the intracellular secretion of CCL3/5, IFN-γ, and TNF-α in CD8+ T cells ( < 0.05), which inhibited p24 levels in CD4+ T cells ( = 0.002), and reduced HIV-1 integrated DNA levels ( = 0.012). Furthermore, the secretion levels of IFN-γ, TNF-α, and GZMB in NK cells and proportion of CD8+ T cells significantly increased following co-culture. These alterations were found to be markedly inversely associated with reservoir size and reactivation. However, these effects were observed in PBMCs from immunological responders (CD4+ T cell count > 350 cells/µL) rather than nonresponders. Tα1 enhances CD8+ T cell function, promotes T proliferation, and suppresses reservoir size and reactivation via IL-15 pathway activation in dendritic cells, which warrants testing in functional cure trials in the future.
Neoadjuvant immunochemotherapy plus thymalfasin in locally advanced gastric cancer: a prospective clinical trial.
Xu H, Li F, Li B, Yang D, Liu T, et al. — 2026
BACKGROUND: Neoadjuvant immunochemotherapy has emerged as a promising strategy for locally advanced gastric and gastroesophageal junction (G/EGJ) adenocarcinoma, but a substantial proportion of patients derive limited benefit. Thymalfasin is an immunomodulatory peptide that may amplify antitumor immunity while attenuating toxicity. We conducted a phase II trial to evaluate anti-PD-1 plus SOX (S-1 and oxaliplatin) immunochemotherapy combined with thymalfasin as neoadjuvant treatment for G/EGJ adenocarcinoma. METHODS: The prospective trial enrolled patients aged 18-75 with cStage III G/EGJ adenocarcinoma, ECOG 0-1, and adequate organ function. Treatment included three 21-day cycles of serplulimab (anti-PD-1) plus SOX (S-1 and oxaliplatin) and 9 weeks of thymalfasin, followed by curative gastrectomy. The primary endpoint was pathological complete response (pCR). Secondary endpoints included major pathological response (MPR), safety, survival, and other efficacy measures. Peripheral immune remodeling was assessed by flow cytometry, and bulk RNA sequencing of peripheral blood mononuclear cells (PBMCs) interrogated thymalfasin-associated transcriptional programs. RESULTS: Thirty patients were enrolled and all underwent curative-intent minimally invasive gastrectomy. pCR was achieved in 30.0% (9/30), and MPR in 56.7% (17/30). ypN0 status was observed in 63.3% (19/30), with N-stage downstaging in 80.0% (24/30). At a median follow-up of 14.0 months (range 10.0-17.2), only one retroperitoneal nodal relapse had occurred at 14.4 months after diagnosis; no deaths were documented. Any-grade adverse events (AEs) occurred in 93.3% of patients, grade ≥ 3 AEs in 26.7%, and immune-related AEs in 23.3%. Flow cytometry showed expansion of CD8⁺ T cells with increased CD69 expression and a concurrent reduction in HLA-DR-positive T cells, suggesting dynamic remodeling from broad systemic activation toward a more focused effector or memory response. RNA-seq revealed thymalfasin-associated upregulation of genes involved in antigen processing and presentation, type I interferon signaling, and identified immune co-expression modules linked to treatment and response. CONCLUSIONS: Neoadjuvant serplulimab, SOX, and thymalfasin produced encouraging pathological response, substantial nodal clearance, and an acceptable safety profile in stage III G/EGJ adenocarcinoma. Peripheral immune and transcriptomic profiling are consistent with a hypothesis in which thymalfasin may help preserve and coordinate systemic antitumor immunity without excessive toxicity. These findings warrant further larger randomized trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06461910, 2024-06-14.