Preclinical
This study investigated why chemotherapy often fails to generate robust anti-tumor immunity and how the endogenous peptide thymosin alpha-1 (Tα-1) might address this gap. The researchers first observed that circulating levels of Tα-1 were reduced after chemotherapy in both cancer patients (across multiple tumor types) and tumor-bearing mice. Mechanistically, the study found that chemotherapy-induced cancer cell death produces apoptotic bodies (ABs) that are poorly immunogenic. Tα-1 was shown to bind to these ABs and interact specifically with AB-associated microRNAs—particularly miR146a-5p—protecting them from degradation by lysosomal RNase A inside dendritic cells (DCs). This protection allowed miR146a-5p to activate Toll-like receptor 7 (TLR7), which in turn licensed DC maturation, migration to tumor-draining lymph nodes, and presentation of tumor antigens to CD8+ T cells. In mouse models, therapeutic Tα-1 supplementation synergized with chemotherapy to suppress established tumors in a TLR7-dependent and miR146a-5p-dependent manner. Limitations include that mechanistic and therapeutic efficacy data are primarily from mouse models, with human data limited to observational measurements of circulating Tα-1 levels.
Cancer research · Jun 2026DOI ↗ Review
This review examines the rationale and emerging evidence for combining Thymosin α1 (Tα1) — a naturally occurring, pleiotropic immunomodulatory peptide — with immune checkpoint inhibitors (ICIs) in the treatment of solid tumors. The authors first outline the biological characteristics of Tα1, highlighting its dual role in enhancing immune competence (e.g., promoting T-cell maturation and activation) while simultaneously regulating excessive immune responses. They then synthesize preclinical and clinical evidence suggesting that Tα1 may address key limitations of ICI monotherapy, including tumor heterogeneity, immunosuppressive tumor microenvironments, and immune-related adverse events (irAEs). The review argues that Tα1 can synergistically remodel the tumor immune microenvironment when combined with ICIs, potentially improving overall response rates. Preliminary clinical findings cited in the review indicate promising efficacy and manageable safety profiles for the combination. The authors acknowledge that the current evidence base relies heavily on early-phase or smaller studies and explicitly call for large-scale, long-term clinical trials to validate sustained benefits. As a narrative review, it does not generate new primary data, and conclusions are limited by the quality and scale of the underlying studies reviewed.
Frontiers in immunology · May 2026DOI ↗ Limited · humanPreprint
This prospective cohort study investigated whether adjunctive thymosin alpha 1 (Thα1) combined with intravenous immunoglobulin (IVIG), initiated 8–10 days after rituximab, could reduce pulmonary adverse events (PAEs) in 379 patients with B-cell lymphoma (BCL) receiving R-CHOP chemotherapy. Patients were assigned to either standard R-CHOP alone (n=164) or R-CHOP plus Thα1-IVIG (n=215); the study was conducted over approximately 11 years. The study found that the Thα1-IVIG group had a notably lower rate of overall PAEs (13.0% vs. 31.7%), with reductions in both infectious pulmonary events and interstitial pulmonary disease. Five-year event-free survival also appeared to favor the adjunctive group. Multivariable Cox proportional hazards models were used to identify independent risk and protective factors. Key limitations include the non-randomized, observational design (patients were not randomly assigned), potential for selection bias and confounding, the preprint status of the manuscript (not yet peer-reviewed), the single-study nature of the findings, and the lack of blinding. These factors substantially limit causal interpretation of the results, and findings should be considered hypothesis-generating pending confirmatory randomized controlled trials.
Unknown journal · Apr 2026DOI ↗ Animal only
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.
Journal of gastroenterology and hepatology · Mar 2026DOI ↗ Moderate · human
This open-label randomized controlled trial (NCT03082885) enrolled 73 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), randomizing them to standard medical therapy (SMT, n=38) or SMT plus Thymosin α1 (Tα1, n=35), with a primary endpoint of 90-day transplant-free survival. Using flow cytometry and ELISA, researchers characterized peripheral immune cell subsets and serum cytokines at baseline and over follow-up. The study found that 90-day survivors had higher baseline effector T (TE) cell proportions, lower regulatory T cells (Tregs), and higher pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) compared to non-survivors. Non-survivors developed a progressive hyperinflammatory trajectory over time. Tα1 treatment was associated with improved 90-day transplant-free survival, reduced Treg frequencies (including CD226 low/- Treg subsets) at weeks 4–8, and moderation of late-stage hyperinflammation without suppressing early immune activation. The authors conclude Tα1 may rebalance immune responses in ACLF. Key limitations include the open-label design, relatively small sample size, and a single-center context, which may limit generalizability.
Immunopharmacology and immunotoxicology · Mar 2026DOI ↗ In vitro
This in vitro study investigated how Thymosin α1 (Tα1) may help reduce the HIV-1 viral reservoir by acting on immune cells. Researchers differentiated THP-1 cells into monocyte-derived dendritic cells (MoDCs) and co-cultured them with peripheral blood mononuclear cells (PBMCs) obtained from people living with HIV-1 (PLWH). The study found that Tα1 stimulation of MoDCs triggered secretion of the IL-15/IL-15 receptor alpha (IL-15/RA) complex, which was associated with enhanced CD8+ T cell and NK cell functionality — including increased secretion of IFN-γ, TNF-α, and granzyme B (GZMB) — along with reductions in intracellular HIV-1 p24 levels and integrated HIV-1 DNA. Notably, these effects were only observed in PBMCs from immunological responders (CD4+ T cell count >350 cells/µL) and not in non-responders. Key limitations include reliance on an in vitro cell line model (THP-1) rather than primary human dendritic cells, lack of an in vivo component, and the correlational nature of many associations. The authors suggest that Tα1's IL-15 pathway activation in dendritic cells could be a candidate mechanism for functional HIV cure strategies, warranting future clinical investigation.
Virulence · Mar 2026DOI ↗ Limited · human
This case report describes a nasopharyngeal carcinoma patient who developed severe multisystem immune-related adverse events (irAEs) following combination treatment with sintilimab (a PD-1 immune checkpoint inhibitor) and thymosin alpha-1 (Tα1), an immunomodulatory peptide. The patient reportedly experienced high fever, skin rash, interstitial pulmonary edema, and multiple organ failure. The authors trace the clinical course from symptom onset through regression and use this case to discuss the potential risks of combining immune checkpoint inhibitors (ICIs) with immunomodulatory agents, suggesting that such combinations may trigger immune overactivation beyond what either agent causes alone. The paper reviews relevant literature to contextualize the case and proposes management strategies for clinicians encountering similar presentations. Key limitations include the inherent constraints of single-patient case reports: causality cannot be firmly established, findings are not generalizable, and confounding factors (e.g., underlying disease burden, other medications) cannot be fully excluded. The authors emphasize the need for heightened clinical vigilance when combining ICIs with immunomodulators like Tα1.
Clinical case reports · Feb 2026DOI ↗ In vitro
This study investigated whether Thymosin α1 (Tα1), an endogenous thymic peptide known to modulate immune function, could enhance CD8+ T cell-mediated killing of breast cancer cells. Researchers isolated CD8+ T cells from peripheral blood of ten healthy donors and tested them under four conditions: unstimulated, CD3/CD28-stimulated, Tα1-treated, or exhaustion-rescue. Cytotoxic activity was assessed against MDA-MB-231 breast cancer cells and CD44+ cancer stem-like cells. The study reported that Tα1 treatment significantly increased cancer cell apoptosis, suppressed tumor cell proliferation, and boosted granzyme B secretion compared to CD3/CD28 stimulation alone. In artificially exhausted T cells, Tα1 partially restored effector function and reduced expression of exhaustion markers PD-1, TIM-3, and LAG-3. Complementary bioinformatic analysis of TCGA-BRCA data (n=1,112) using a four-gene Tα1 Response Index correlated with antigen presentation and cytotoxic gene programs. Key limitations include the small donor sample (n=10), use of healthy donor rather than patient-derived T cells, an in vitro experimental design, and the exploratory nature of the transcriptomic index. Results may not directly translate to in vivo or clinical settings.
Human immunology · Jan 2026DOI ↗ Review
This review paper examines the relationship between aging and Thymosin Alpha-1 (Tα1), a peptide hormone naturally produced by the thymus gland. The authors describe how age-related thymic involution leads to reduced T-cell production, chronic low-grade inflammation (inflammaging), and heightened vulnerability to age-related diseases — a phenomenon collectively termed immunosenescence. The paper outlines Tα1's proposed mechanisms of action, including stimulation of T-cell differentiation, enhancement of thymic output, and modulation of dendritic cells and macrophages. It also highlights Tα1's immunomodulatory, anti-inflammatory, and antioxidant properties. The authors review preclinical and clinical evidence suggesting Tα1 may improve vaccine responses in elderly populations and help counteract immunosenescence. Additionally, the paper discusses Refnot, a hybrid fusion drug combining Tα1 with tumor necrosis factor alpha (TNFα), which reportedly retains antitumor activity while exhibiting reduced toxicity compared to TNFα alone. The authors conclude that Tα1 holds therapeutic promise for age-related immune dysfunction but emphasize that long-term efficacy and safety data in geriatric populations remain limited and that further research is warranted. As a review, this paper synthesizes existing literature rather than presenting original experimental data.
International journal of molecular sciences · Nov 2025DOI ↗ Limited · human
This retrospective, single-arm study evaluated the effects of a 7-day loading dose of thymosin α1 (Tα1) on peripheral blood lymphocyte counts, as well as the safety and efficacy of combining Tα1 with hypofractionated radiotherapy and PD-1 inhibitors in 48 patients with advanced or refractory cancers. Peripheral blood T cells, B cells, and natural killer cells were measured by flow cytometry before and after Tα1 administration. The study found that the 7-day Tα1 course was associated with statistically significant increases in total T cells, CD4+ T cells, and CD8+ T cells. Secondary outcomes including objective response rate, disease control rate, progression-free survival, and overall survival were also reported alongside adverse event data, with the authors characterizing the safety and efficacy profiles as satisfactory. Key limitations include the retrospective, non-randomized, single-arm design; the small and heterogeneous patient population spanning multiple tumor types; a median follow-up of only 13.7 months, which may be insufficient to assess long-term survival and late toxicities; and the absence of a control group, making it difficult to isolate Tα1's contribution. The authors acknowledge these findings are exploratory and call for larger, randomized, homogenous cohort studies to validate results.
Cancer management and research · Nov 2025DOI ↗ Animal only
This study investigated the role of ferroptosis (a form of iron-dependent regulated cell death) in pulpitis and evaluated whether thymosin α1 (Tα1) could mitigate this process. Using single-cell RNA sequencing (scRNA-seq) of tissue from 3 pulpitis and 3 healthy pulp samples, researchers identified 12 distinct cell clusters and found that differentially expressed ferroptosis-related genes (DE-FRGs) were broadly present across clusters in pulpitis tissue. Elevated reactive oxygen species (ROS) and Fe²⁺ levels, alongside reduced GPX4 and elevated PTGS2 expression by immunohistochemistry, suggested active ferroptosis in inflamed pulp. In LPS-stimulated dental pulp cells (DPCs) in vitro, Tα1 treatment was associated with increased GPX4 and FTL expression and reduced inflammatory markers (TNF-α, IL-1β, IL-6) and Fe²⁺ levels. In rat pulpitis models, delivery of prothymosin α (PTMA, the Tα1 precursor) via gelatin sponge or direct injection reduced inflammatory cell infiltration, decreased PTGS2, and increased GPX4. RNA sequencing of LPS-stimulated DPCs confirmed reversal of DE-FRG expression with Tα1 treatment. Key limitations include small human tissue sample sizes (n=3 per group), reliance on animal and cell models for intervention data, and the lack of human clinical trials.
International journal of oral science · Oct 2025DOI ↗ Moderate · humanPreprint
This single-center randomized controlled trial enrolled 171 elderly patients with sepsis-associated acute respiratory distress syndrome (ARDS) to evaluate whether adding thymosin alpha 1 (Tα1) to a background regimen of sivelestat sodium and ambroxol improved outcomes. Participants were assigned to a control group (sivelestat + ambroxol, n=86) or an experimental group (same regimen plus Tα1, n=85) for 7 days; all patients also received high-flow nasal cannula oxygen therapy. The study found that the experimental group demonstrated a higher overall clinical response rate (85.9% vs. 72.1%, P<0.05), reduced mortality, improved survival, and better respiratory function parameters compared with controls. Safety profiles were reported as favorable in both groups. Limitations include the single-center design, which may reduce generalizability; the relatively short 7-day intervention window; and the fact that the paper is a preprint, meaning it has not yet undergone formal peer review. The combination of co-interventions (sivelestat and ambroxol alongside Tα1) also makes it difficult to isolate the independent contribution of Tα1 to the observed outcomes.
Unknown journal · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy of thymosin α1 (Tα1), a synthetic immunomodulatory peptide, in treating sepsis. Researchers searched for prospective clinical studies measuring 28-day mortality in sepsis patients treated with Tα1 (excluding combination therapy studies), ultimately including 11 randomized controlled trials (RCTs) totaling 1,927 patients. The overall meta-analysis found a statistically significant reduction in 28-day mortality associated with Tα1 (OR 0.73, 95% CI: 0.59–0.90). However, when analysis was restricted to high-quality trials or multicenter trials — considered more rigorous subsets — the mortality benefit was no longer statistically significant (ORs 0.82 and 0.86, respectively). A heterogeneity of treatment effects analysis drawing on individual patient data from two large multicenter RCTs (representing ~75% of total patients) suggested potential benefits in subgroups with cancer (moderate credibility), diabetes, and coronary heart disease (both low credibility). Trial sequential analysis indicated the current evidence base is underpowered. The authors concluded that while Tα1 shows potential, its benefits appear to vary across patient subgroups, and personalized immunotherapy approaches warrant investigation in future, adequately powered trials.
Frontiers in cellular and infection microbiology · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy of Thymosin alpha 1 (Tα1), an immunomodulatory peptide, in patients with severe acute pancreatitis (SAP). Researchers searched five major databases through February 2025 and identified five randomized controlled trials encompassing 706 SAP patients, comparing Tα1 treatment against non-Tα1 controls. The pooled analysis found that Tα1 was associated with increased percentages of CD4+ T cells and improved CD4+/CD8+ ratios, suggesting a positive effect on immune cell balance and reduction of immune suppression. Lower-dose Tα1 was associated with significantly reduced C-reactive protein (CRP) levels, an inflammation marker. Tα1 was also associated with a potential reduction in extrapancreatic infection risk. The authors concluded that Tα1 may regulate immune cell balance and exert anti-inflammatory effects in SAP patients, potentially improving prognosis. Key limitations include the small number of included trials (n=5), the relatively modest total patient population, heterogeneity in dosing protocols, and the predominance of studies from a single country (China), which may limit generalizability. The authors noted that further research is needed to validate these findings.
Frontiers in immunology · Jun 2025DOI ↗ Insufficient
This paper presents the protocol for PANDA II, a multicenter randomized controlled trial investigating whether thymosin alpha 1 (Tα1) supplementation can prevent organ dysfunction following acute type A aortic dissection (ATAAD) surgical repair. A total of 330 patients will be equally randomized to receive either Tα1 plus standard care or placebo plus standard care. The primary endpoint is the difference in mean postoperative Sequential Organ Failure Assessment (SOFA) scores measured daily through postoperative day 7. The scientific rationale centers on Tα1's proposed ability to rebalance post-operative immune dysregulation, thereby reducing systemic inflammatory response syndrome (SIRS)-mediated organ injury. As a protocol paper, no efficacy or outcome data are yet available. Limitations inherent to this stage include the absence of results, potential challenges in blinding given Tα1's immunological activity, and the complexity of standardizing post-surgical care across multiple centers. The trial is registered on ClinicalTrials.gov (NCT05339529). Findings will be published once the trial is completed, and this protocol represents a foundational step toward establishing evidence for Tα1 as a novel therapeutic strategy in this high-risk surgical population.
Future cardiology · May 2025DOI ↗ Limited · human
This small open-label proof-of-concept study investigated whether thymosin alpha-1 (Tα1), a thymic peptide hormone, might reduce depressive symptoms in five patients with common variable immunodeficiency (CVID) who also had a comorbid depressive episode. The rationale was that CVID patients share immune abnormalities with major depressive disorder (MDD) patients — notably reduced naïve T cells and premature T-cell senescence — and that Tα1 can stimulate thymic output of naïve T cells, potentially improving mood via immune-limbic system pathways. Patients received Tα1 subcutaneously over eight weeks and were assessed using the Hamilton Depression Rating Scale (HDRS) alongside immune biomarkers. All five CVID patients showed reductions in HDRS scores (average 52%), compared to a 36% average reduction in a non-randomized contrast group of 42 MDD patients receiving treatment as usual. Naïve/memory T-cell ratios improved in all five patients, and IL-6 levels decreased in four of the five. However, depressive and immune improvements were not sustained in a subsequent eight-week wash-out period for the more severely affected patients. Key limitations include the very small sample size (n=5), lack of a placebo control, open-label design, and use of a non-matched contrast group. The authors conclude that larger placebo-controlled trials are warranted.
Brain, behavior, & immunity - health · Jan 2025DOI ↗ Review
This review article explores phenotypic drug discovery (PDD) as a research framework and uses thymosin alpha-1 (Tα1), a thymic peptide hormone, as a central case study. PDD is described as an approach that screens compounds based on observable effects in cells, tissues, or whole organisms, without requiring prior knowledge of a specific molecular target. The authors contrast PDD with target-based drug discovery and argue that because disease definitions are largely symptom-based, therapeutic development can benefit from a phenotypic lens. The paper discusses how Tα1 has been evaluated in both preclinical and clinical settings, highlighting its complex immunomodulatory properties and its involvement in host-microbe metabolic interactions across multiple targets and metabolites. The authors also address challenges inherent to PDD, including hit validation and target deconvolution, and suggest that advances in big data analytics may help overcome these hurdles. The article further argues that Tα1's broad therapeutic utility can be meaningfully situated within the PDD framework and the modern precision medicine era. As a narrative review, it does not present original experimental data, and its conclusions are shaped by the selection and interpretation of existing literature.
Frontiers in medicine · Jun 2024DOI ↗ Limited · human
This prospective, open-label, randomized pilot trial (NCT04487444) evaluated the preliminary efficacy and safety of thymalfasin (synthetic Thymosin-α-1, or Tα1) compared with standard of care in 49 hospitalized COVID-19 patients presenting with both hypoxemia and lymphocytopenia. The primary clinical outcome—rate of clinical recovery—was numerically higher in treated patients receiving either low-flow or high-flow baseline oxygen support, but neither difference reached statistical significance (subdistribution hazard ratios of 1.48 and 1.28, respectively, with wide confidence intervals crossing 1.0). A notable immunological finding was that treated patients on baseline low-flow oxygen had, on average, 3.84 times more CD4+ T cells on day 5 compared with day 1, versus controls (P = .01), suggesting faster T-cell reconstitution. Nine serious adverse events occurred in the treatment group but were adjudicated as unrelated to Tα1. Key limitations include the small sample size (n=49), open-label design (no blinding), and lack of statistical power to draw definitive efficacy conclusions. The authors suggest Tα1 may have a role in managing COVID-19-related immunosuppression, but larger trials are needed to confirm these preliminary findings.
The Journal of infectious diseases · Jan 2023DOI ↗