Thymosin Alpha-1

What it is

Thymosin Alpha-1 (Tα1) is a 28-amino-acid endogenous peptide originally isolated from thymic tissue and processed in vivo from prothymosin alpha by a lysosomal asparaginyl endopeptidase (legumain). It functions as a biological response modifier with pleiotropic immunomodulatory activity. Tα1 acts through Toll-like receptors (TLRs), particularly TLR7, in both myeloid and plasmacytoid dendritic cells, leading to activation of downstream signaling pathways and production of immune-related cytokines. In the tumor microenvironment, Tα1 binds to phosphatidylserine on apoptotic tumor cells, is internalized by macrophages, and activates SHIP1 via TLR7/MyD88, reversing M2 polarization of tumor-associated macrophages and enhancing antitumor CD4+ and CD8+ T cell responses. Tα1 also acts as a microRNA chaperone: it binds tumor apoptotic body-borne miR-146a-5p and protects it from lysosomal RNase A degradation, enabling TLR7 activation in dendritic cells, which licenses DC maturation, migration, and tumor antigen presentation. Tα1 stimulates T-cell differentiation and proliferation, enhances thymic output as measured by T-cell receptor excision circles, and restores exhausted T cells (PMID 27442287; PMID 39339). It suppresses myeloid-derived suppressor cells (MDSCs) via VEGF/HIF-1α downregulation, modulates cytokine/chemokine production, and upregulates CD40/CD40-L while downregulating PDL-1/PD-1 in dendritic cell–T cell immune synapses. The peptide exhibits anti-inflammatory and antioxidant properties (PMID 30063866; PMID 31067016) and has an intrinsically disordered structure that acquires secondary structure (alpha-helix residues 14–26; double β-turns in N-terminal residues 1–12) under structure-inducing conditions (PMID 27450728; PMID 22115779).

Class: Endogenous thymic peptide hormone / immunomodulatory polypeptide (28 amino acids)

What it's studied for

• Sepsis / septic shock (immunomodulation and mortality reduction) Human RCT
  • No statistically significant difference in 28-day all-cause mortality between Tα1 (subcutaneous q12h × 7 days) and placebo (HR 0.99; 95% CI 0.77–1.27; P=0.93). Subgroup analysis suggested potential benefit in patients ≥60 years (HR 0.81) and diabetics (HR 0.58) but harm signal in patients <60 years (HR 1.67). No signif PMID 39814420 Wu J et al. BMJ 2025 (TESTS trial, phase 3 RCT, n=1089, China)
  • Review of clinical studies concluded that single or combined Tα1 treatment reduced mortality, improved HLA-DR expression on monocytes, and diminished secondary infection incidence in sepsis, though heterogeneity of sepsis populations limits generalizability. PMID 30063864 Pei F et al. Expert Opinion on Biological Therapy 2018 (review)
• COVID-19 treatment (immune restoration, mortality reduction) Mixed
  • Tα1 significantly reduced mortality in severe COVID-19 patients (11.11% vs 30.00%, P=0.044). Restored T-cell numbers (CD4+ and CD8+), enhanced thymic output (TRECs), and reduced PD-1 and Tim-3 expression on CD8+ T cells. Patients with CD8+ <400/μL or CD4+ <650/μL gained more benefit. PMID 32442287 Liu Y et al. Clinical Infectious Diseases 2020 (retrospective, n=76 severe COVID-19, Wuhan)
  • Pooled data showed significantly lower COVID-19 mortality with Tα1 (RR 0.59; 95% CI 0.37–0.93, P=0.02). No significant difference in need for mechanical ventilation or hospital length of stay. High heterogeneity (I²=84%). PMID 37845598 Soeroto AY et al. Inflammopharmacology 2023 (meta-analysis, 8 studies)
  • After confounding adjustment, Tα1 use was associated with higher non-recovery rate (OR 1.5, 95% CI 1.1–2.1). Increased risk particularly in patients with SOFA ≥2, ICU admission, and lower PaO2/FiO2. Later initiation associated with worse outcomes. PMID 34408744 Liu J et al. Frontiers in Immunology 2021 (multicenter cohort, n=2282, China)
  • No significant difference in CD4+ or CD8+ T-cell count restoration between Tα1 and non-Tα1 groups. Tα1 was associated with significantly longer virus clearance duration. Authors concluded Tα1 may have no benefit on T-cell restoration or viral clearance. PMID 34149679 Wang Z et al. Frontiers in Immunology 2021 (retrospective, n=275, Shanghai)
  • Tα1 (thymalfasin) increased CD4+ T cells 3.84× more on day 5 vs day 1 in low-flow oxygen patients (P=0.01). Clinical recovery differences were not statistically significant. Nine serious adverse events deemed unrelated to Tα1. PMID 36056913 Shehadeh F et al. Journal of Infectious Diseases 2023 (pilot RCT, n=49)
  • In PASC individuals, ex vivo Tα1 improved restoration of appropriate immune responses, most evident in those with more severe acute illness and specific systemic/psychiatric PASC symptoms. PMID 36989892 Minutolo A et al. International Immunopharmacology 2023 (ex vivo study, PASC patients)
  • Multivariate Cox analysis showed Tα1 improved 28-day survival in COVID-19 (HR 0.45; 95% CI 0.25–0.84, P=0.012). Tα1 group had significantly greater CRP reduction at 7 days. PMID 35728851 Wang T et al. Zhonghua wei zhong bing ji jiu yi xue 2022 (retrospective cohort, n=95)
• Chronic Hepatitis B (antiviral and immune enhancement) Human RCT
  • Thymalfasin reviewed as immunoregulatory agent enhancing Th1 response in chronic HBV; shown to trigger lymphocyte maturation, augment T-cell function, and promote immune reconstitution. PMID 15546254 Liaw YF. Journal of Gastroenterology and Hepatology 2004 (review)
  • Subcutaneous Tα1 1.6 mg twice weekly for 6 months: complete response (ALT normalization + HBV DNA and HBeAg loss) at end of 6-month follow-up in 48.3% of Tα1 patients vs 27.3% IFN-α patients. Tα1 was well tolerated with no side effects; IFN-α had more adverse effects. PMID 17075991 You J et al. World Journal of Gastroenterology 2006 (RCT, n=62)
  • At end of follow-up, Tα1 showed significantly better virological (OR 3.71), biochemical (OR 3.12), and complete response (OR 2.69) rates compared to IFN-α, although IFN-α showed greater response at end of treatment. PMID 18078676 Yang YF et al. Antiviral Research 2008 (meta-analysis, 4 RCTs, n=199)
  • Lamivudine + Tα1 combination significantly superior to lamivudine monotherapy: ALT normalization (80.2% vs 68.8%), virological response (84.7% vs 74.9%), HBeAg seroconversion (45.1% vs 15.2%). PMID 19467157 Zhang YY et al. Virology Journal 2009 (meta-analysis, 8 RCTs, n=583)
  • IFN + Tα1 combination markedly superior to IFN monotherapy in HBV-DNA negative rate, ALT normalization, HBeAg loss, and seroconversion rates at end of treatment and follow-up, with no increase in adverse effects. PMID 21272455 Mao HY et al. Chinese Journal of Hepatology 2011 (meta-analysis, 7 RCTs, n=535)
  • ETV + Tα1 showed higher complete response (RR=1.18), better early HBV DNA undetectable and HBeAg loss rates at 24 weeks, improved biochemical parameters and liver fibrosis, and significantly fewer adverse events (RR=0.48) vs ETV monotherapy. No significant difference at 48–52 weeks. PMID 33076834 Peng D et al. BMC Gastroenterology 2020 (meta-analysis, 7 RCTs, n=1144)
• Hepatocellular carcinoma (adjuvant post-resection) Human observational
  • Tα1 as adjuvant therapy after curative resection of solitary HBV-related HCC independently improved both OS (HR=0.308; 95% CI 0.175–0.541) and RFS (HR=0.381; 95% CI 0.229–0.633) before and after propensity score matching. Immunological response improved in Tα1 group. PMID 34011034 He L et al. Medicine 2021 (retrospective, n=468, PSM analysis)
• Chronic Hepatitis C (combination immunotherapy) Human RCT
  • Tα1 1.6 mg SC twice weekly added to peginterferon alfa-2a + ribavirin for 48 weeks: ITT SVR rates similar between Tα1 (12.7%) and placebo (10.5%; P=0.407). Among patients completing 48 weeks, SVR significantly higher with Tα1 (41.0% vs 26.3%, P=0.048). No difference in adverse event incidence. PMID 22233415 Ciancio A et al. Journal of Viral Hepatitis 2012 (RCT, n=552)
  • Multiple clinical trials of Tα1 in HCV have produced mixed results; large RCTs failed to conclusively support Tα1's role in combination IFN-based therapies for HCV. PMID 20536461 Sherman KE. Annals of the New York Academy of Sciences 2010 (review)
• Cancer immunotherapy (solid tumors, NSCLC, lymphoma) Mixed
  • Tα1 reversed M2 polarization of TAMs during efferocytosis via TLR7/SHIP1/TBK1 axis, reducing IL-10 and enhancing CD4+/CD8+ tumor-infiltrating T cells. Combined with epirubicin, markedly suppressed tumor growth in vivo. PMID 35364609 Wei Y et al. Cancer Research 2022 (in vivo mouse breast cancer model + human tumor samples)
  • Tα1 inhibited M-MDSC migration to tumor microenvironment by suppressing VEGF production via HIF-1α downregulation in NSCLC. Promoted MDSC apoptosis by reducing Bcl-2/BAX ratio. PMID 32942159 Yang Z et al. Biomedicine & Pharmacotherapy 2020 (in vitro + mouse NSCLC model)
  • Tα1 reprogrammed M2-polarized TAMs induced by oncolytic adenovirus toward antitumoral phenotype, reduced Tregs in TME, and enhanced antitumor efficacy via CD8+ T cells in vivo. PMID 39357524 Liu K et al. Cell Reports Medicine 2024 (mouse + human in vitro, oncolytic adenovirus model)
  • Tα1 acts as microRNA chaperone protecting miR-146a-5p from lysosomal degradation, enabling TLR7 activation in DCs. Therapeutic Tα1 supplementation showed strong synergy with chemotherapy to control established tumors in a TLR7-dependent, miR-146a-5p-high manner. PMID 42295795 Wei Y et al. Cancer Research 2026 (mouse + human samples)
  • Gemcitabine + Tα1 combination inhibited NNKTL cell growth, EMT, and EBV viral load more effectively than either alone; enhanced apoptosis and autophagy via PI3K/AKT/mTOR inhibition in vitro and in xenograft models. PMID 34119916 Chen M et al. International Immunopharmacology 2021 (in vitro + in vivo xenograft, NNKTL)
  • PD-1 inhibitor + SBRT + GM-CSF + Tα1 combination in one mTNBC patient: partial response with target lesion regression of -78.97%, abscopal effects, stable hematological indexes. Grade 2 skin reaction occurred, resolved with antiallergic treatment. PMID 39183403 Yu J et al. Medicine 2024 (case report, mTNBC)
• Vaccine immune enhancement (influenza, elderly/immunocompromised) Human RCT
  • Tα1 (Zadaxin) at 3.2 mg or 6.4 mg added to adjuvated H1N1v influenza vaccine improved GMT and GMR of HI on Day 21 and seroconversion rates vs vaccine alone in hemodialyzed patients. CHMP criteria fully met in Tα1 groups. No adverse events related to Tα1. PMID 22178096 Carraro G et al. Vaccine 2012 (pilot RCT, n=99, hemodialyzed patients)
  • Review concluded Tα1 (Zadaxin) ameliorates influenza vaccination performance in elderly and at-risk subjects by enhancing T-cell, dendritic cell, and antibody responses. PMID 22010537 Panatto D et al. Journal of Preventive Medicine and Hygiene 2011 (review)
• Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) Human RCT
  • Tα1 significantly improved FEV1, FEV1/FVC ratio, arterial PaO2, reduced PaCO2, shortened hospital stay (MD=-5.39 days), increased CD4+ T lymphocytes and CD4+/CD8+ ratio, and decreased CD8+ counts compared with routine treatment alone. PMID 39648386 Cao A et al. JCPSP 2024 (meta-analysis, 39 RCTs, n=3329)
• Severe acute pancreatitis (immune regulation and infection prevention) Human RCT
  • Tα1 increased CD4+ percentages (MD=4.53) and CD4/CD8 ratio (MD=0.42). Lower-dose Tα1 significantly reduced CRP levels (MD=-30.12 mg/L); higher-dose showed no significant CRP difference. Reduced overall extrapancreatic infection incidence (RR=0.56), especially blood and abdominal infections. Reduced APACHE II score (MD= PMID 40599771 Tian Y et al. Frontiers in Immunology 2025 (meta-analysis, 5 RCTs, n=706)
• HIV-1 infection (immune reconstitution adjunct) Mixed
  • Review of in vitro and in vivo studies concluded that Tα1 demonstrates ability to restore immune system homeostasis in HIV-1 infection, including conditions where antiretroviral therapy leaves incomplete immune reconstitution. Discusses persistent inflammation and inefficient cytotoxic T-cell response as contexts for T PMID 28106477 Matteucci C et al. Future Microbiology 2017 (review)
• Cystic fibrosis (immunomodulation and extrapulmonary effects) Animal studies only
  • Tα1 restored barrier integrity and immune homeostasis in the inflamed gut of CF mice and mice with metabolic syndrome. Protective effects extended to pancreas and liver in murine models of CF extrapulmonary complications. PMID 33071052 Bellet MM et al. European Journal of Medicinal Chemistry 2021 (murine CF models)
  • Two independent laboratories found Tα1 devoid of activity on mutant F508del-CFTR and on calcium-activated chloride channel (CaCC). Anti-inflammatory role not excluded but anion transport correction not demonstrated. PMID 29415893 Tomati V et al. JCI Insight 2018 (in vitro, human bronchial epithelial cells + cell lines)
  • Six independent laboratories failed to demonstrate F508del-CFTR correction by Tα1. DMSO-related changes in Tα1 were found reversible. Immunomodulatory effects not excluded but CFTR corrector utility not supported. PMID 31311979 Armirotti A et al. Scientific Reports 2019 (in vitro, multiple cell types)
• HCMV infection (in vitro immunomodulation) In vitro only
  • Tα1 increased CD40, CD80, TIM-3 expression and TNFα production while decreasing PDL-1 on pDCs. Modulated TNFα, IFNγ, IL-2 in CD4+ and CD8+ T cells; enhanced polyfunctionality of CD8+ T cells during HCMV infection. CD40/CD40-L upregulated; PDL-1/PD-1 downregulated. PMID 38149577 Espinar-Buitrago MS et al. International Immunopharmacology 2023 (in vitro, PBMCs)
  • Tα1 + polyanionic carbosilane dendrimers (PCDs) showed synergistic effects on DC activation and maturation during early HCMV infection. Tα1+G2-S24P increased co-receptor expression, IFNγ in T cells, and Treg functionality; Tα1+G2S16 had opposite effects on Treg. PMID 38396631 Espinar-Buitrago MS et al. International Journal of Molecular Sciences 2024 (in vitro, PBMCs + PCDs)
• Aging and immunosenescence Mixed
  • Review concludes Tα1 can improve vaccine response in elderly and mitigate immunosenescence by stimulating T-cell differentiation, enhancing thymic output, and modulating DC and macrophage activity. A Tα1-TNFα hybrid drug is discussed as a therapeutic approach for age-related immune dysfunction. PMID 41373628 Simonova MA et al. International Journal of Molecular Sciences 2025 (review)
• Non-small cell lung cancer (NSCLC, adjuvant and chemoradiation setting) Human observational
  • Recent studies cited by author indicate Tα1 significantly improved OS in surgically resectable NSCLC and liver cancers in adjuvant setting; reduced chemoradiation-induced lymphopenia and pneumonia in locally advanced unresectable NSCLC. Specific study citations are embedded in the review narrative. PMID 36871535 Mao L. International Immunopharmacology 2023 (narrative review)

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.