Data from the Scientific Registry of Transplant Recipients (SRTR) database (https://www.srtr.org/) were utilized in this study to investigate patients undergoing various transplantation procedures. As a widely recognized resource in solid organ transplantation (SOT) research, the SRTR database served as the primary data source for this investigation.

AR was defined according to the diagnostic criteria established by the Transplantation Society. Corticosteroids included prednisone, methylprednisolone (Solu-Medrol), and Medrol. Calcineurin inhibitors (CNIs) included tacrolimus (Prograf), cyclosporine formulations (Neoral, Sandimmune, and Gengraf), extended-release tacrolimus (Astagraf XL), and generic equivalents (generic Prograf for tacrolimus and EON for cyclosporine). mTOR inhibitors included sirolimus (Rapamune) and everolimus (Zortress). Antiproliferative agents consisted of azathioprine (AZA), mycophenolate mofetil (MMF; CellCept), mycophenolic acid (Myfortic), and generic MMF (generic CellCept). Polyclonal/monoclonal antibodies included muromonab-CD3 (OKT3), basiliximab (Simulect), alemtuzumab (Campath), rituximab (Rituxan), daclizumab (Zenapax), antilymphocyte globulin (ALG), thymoglobulin and Atgam. Alkylating agents included cyclophosphamide (Cytoxan). The novel immunosuppressants used were FTY720 (fingolimod) and belatacept (Nulojix).

Survival analysis was performed via the Kaplan–Meier method with log-rank tests. Cox proportional hazards regression models were employed to assess the impact of various immunosuppressants on transplant recipient survival, generating hazard ratios (HRs) with 95% confidence intervals (CIs). Logistic regression analysis was used to evaluate the associations between immunosuppressants and AR risk, and odds ratios (ORs) with 95% CIs were reported. Statistical computations were primarily conducted using RStudio version 4.4 (https://www.rstudio.com/). A significance threshold of P < 0.05 was applied for all inferential analyses.

This study analyzed diverse solid organ transplant (SOT) populations through the Scientific Registry of Transplant Recipients (SRTR) database to evaluate the immunosuppressants impacts on AR and overall survival (OS) across solid organ transplants(Figure 1A). The bubble plot revealed roles of common immunosuppressants in various organ transplant types(Figure 1B). The baseline characteristics of the study cohort, comprising 118,000 liver transplant (LT) recipients, 319,328 kidney transplant (KT) recipients, 46,157 heart transplant (HT) recipients, 25,789 lung transplant (LU) recipients, 6,361 pancreas transplant (PT) recipients, 2,175 intestine transplant (IT) recipients, 517 heart-lung transplant (HL) and 23101 pancreas-kidney transplant (PK), are presented in Table 1.

We analyzed rejection rates across different organ transplants, recipients were stratified into two groups: nonacute rejection (non-AR) and AR. The incidence of AR across transplant types was as follows: LT - 3.79% (n=4,468), KT - 4.58% (n=14,640), HT - 10.64% (n=4,911), LU - 14.50% (n=3,740), PT - 8.33% (n=530), IT - 18.48% (n=402), HL-14.89%(n=77) and PK-3.28%(n=757), as detailed in Table 1.

Kaplan–Meier survival analysis revealed significantly lower overall survival (OS) in recipients who experienced AR than in their rejection-free counterparts (Figure 2, P < 0.001). Notably, the relatively limited sample size of IT and HL recipients may constrain the statistical power of related analyses. Furthermore, baseline characteristics, including age, sex, body mass index (BMI) and ABO blood type, exhibited differential distributions between rejection groups (Table 1); these parameters may confound rejection incidence and clinical outcomes, and further investigation into their synergistic effects in future mechanistic studies is warranted.

To further assess the impact of different immunosuppressants and AR on prognosis, a Cox regression analysis was conducted. The results revealed that AR was a risk factor for OS in all types of SOT (Table 3; Supplementary Figure S6).

By comparing the use of immunosuppressants in various types of transplantation, it was found that cyclosporine (Cyclosporin) significantly reduced the risk of death (HR < 1) in liver transplant (LT), heart transplant (HT), lung transplant (LU), heart-lung transplant (HL), pancreas transplant (PT) and kidney transplant (KT) patients, but had no significant effect in intestine transplant (IT) and pancreas–kidney transplant (PK) patients. Tacrolimus increased the risk of death (HR > 1) in liver transplant (LT), heart transplant (HT), lung transplant (LU), kidney transplant (KT) and heart-lung transplant (HL), patients, but had no significant effect in intestinal transplant (IT), pancreas transplant (PT) and pancreas–kidney transplant (PK) patients. Mycophenolate mofetil (MMF) significantly increased the risk of death (HR > 1) in liver transplant (LT), heart transplant (HT), lung transplant (LU), kidney transplant (KT), heart-lung transplant (HL) and pancreas–kidney transplant (PK) patients, reduced the risk of death (HR < 1) in pancreas transplant (PT), but had no significant effect in intestinal transplant (IT) Overall, the efficacy and risks of different immunosuppressants vary significantly across different transplant types, requiring individualized treatment selection based on the specific transplant type and patient condition(Table 3; Supplementary Figure S6).

Corticosteroids demonstrate marked efficacy in suppressing AR post transplantation. Their mechanism of action primarily involves the formation of receptor–corticosteroid complexes, which are translocated into the nucleus to modulate the transcription of target genes associated with inflammatory and immune responses, thereby exerting dual immunosuppressive and anti-inflammatory effects (4, 29–34). In this study, corticosteroid use was associated with improved survival rates in LT recipients but with reduced survival rates in PK transplant recipients. This discrepancy may be attributed to variations in the duration of corticosteroid therapy and the timing of immunosuppressant withdrawal. Notably, prolonged corticosteroid administration has been linked to dose-dependent adverse effects, including infectious complications, new-onset diabetes mellitus, and osteoporosis, in transplant populations, paradoxically increasing mortality risks over extended follow-up periods (35, 36). Consequently, corticosteroid therapy necessitates careful risk–benefit assessment to balance its therapeutic efficacy against dose-limiting toxicities, with patient-tailored regimens optimized through comprehensive evaluation of recipient-specific comorbidities, immunological risk profiles, and dynamic monitoring of infection biomarkers.

Cyclosporine and tacrolimus, as cornerstone CNIs in transplant immunosuppression, demonstrate critical efficacy in preventing allograft rejection while facing persistent challenges in managing breakthrough immune-mediated complications during post transplantation care (37). CNIs are associated with several clinically significant adverse effects; therefore, vigilant monitoring and management are required. The most consequential complication is dose-dependent nephrotoxicity, which is mediated through dual mechanisms of afferent arteriolar vasoconstriction (via endothelin-1 upregulation) and direct tubular epithelial cell injury, which may compromise long-term allograft function. Additionally, CNIs induce hypertension through increased angiotensin II receptor sensitivity and sodium retention, metabolic disturbances, including hyperlipidemia—characterized by elevated low-density lipoprotein (LDL) cholesterol and triglycerides—frequently occur due to altered apolipoprotein metabolism. Proactive therapeutic drug monitoring (TDM) coupled with individualized CNI target ranges remains paramount in balancing immunosuppressive efficacy with toxicity mitigation (38–41).

Tacrolimus exhibits organ-specific paradoxical effects: The tacrolimus (Prograf) was associated with reduced survival and increased rejection risk in kidney (KT) and liver (LT) transplants. However, in lung transplantation (LU), the tacrolimus (Prograf) significantly lowered rejection risk while paradoxically reducing survival, suggesting an immunosuppression-toxicity imbalance in this organ. Generic tacrolimus formulations were consistently associated with elevated rejection risk and worse survival outcomes across all organ types. This discrepancy may stem from the significant pharmacokinetic variability of tacrolimus in patients and its association with CYP3A5 expression levels and genetic variations, highlighting the importance of personalized treatment for transplant recipients (42–44).

This study found that cyclosporine exerts protective effects AR in most solid organ transplant (SOT) recipients. Interestingly, in HT, the originator cyclosporine formulation emerged as a protective factor against AR, whereas its generic counterparts demonstrated a risk effect. This phenomenon suggests that within the same transplant type, originator and generic immunosuppressants may exert divergent clinical impacts. In the same time, the efficacy of the same immunosuppressant may also vary across transplant types: tacrolimus significantly reduced AR risk in LU recipients while elevating AR risk in KT.

mTOR inhibitors exert immunosuppressive effects by binding to FKBP to form a complex, which effectively inhibits mTOR activation. This inhibition halts cell cycle progression from the G1 phase to the S phase, thereby blocking T-cell activation and proliferation (45–49). mTOR inhibitors may improve outcomes by inhibiting B-cell proliferation and antibody production. In addition to their immunosuppressive effects, mTOR inhibitors also exhibit antitumor and antifibrotic properties, which help reduce the risk of post transplantation malignancies and slow the progression of allograft fibrosis (50–55). However, the use of mTOR inhibitors may be associated with several adverse effects: 1). Increased infection risk: mTOR inhibitors may suppress immune system function, increasing the risk of infections, particularly opportunistic infections; 2). Delayed wound healing: mTOR inhibitors may impair cellular proliferation and differentiation, leading to delayed wound healing. 3). Hyperlipidemia: mTOR inhibitors may disrupt lipid metabolism, resulting in hyperlipidemia; 4). Renal impairment: Certain mTOR inhibitors may cause nephrotoxicity (54, 56–60).

The role of mTOR inhibitors in liver transplantation remains a matter of debate, with findings from some studies suggesting increased survival rates in LT recipients, whereas other studies have revealed no significant benefits (61–64). Therefore, their use carries potential risks, necessitating individualized assessment of patient benefits versus risks.

Antiproliferative agents, indispensable immunosuppressants in organ transplantation, play a critical role in preventing rejection by inhibiting cellular proliferation and immune responses. However, their efficacy and safety profiles vary significantly across different agents, necessitating individualized selection based on transplant type, patient-specific factors, and other clinical considerations. AZA(azathioprine) improved survival in liver and kidney transplants, whereas MMF (CellCept) increased rejection risk and decreased survival in HT. These disparities may stem from differences in immune mechanisms and microenvironments across transplant types. For example, LT recipients may be more susceptible to AMR, against which AZA has stronger inhibitory effects. The availability of generic MMF and mycophenolic acid has expanded therapeutic options, although further validation of their bioequivalence and safety is required. The study findings demonstrate divergent profiles in pharmaceutical stability and immunosuppressive potency among distinct antiproliferative agents, highlighting the imperative for cautious substitution protocols and rigorous therapeutic monitoring during formulation transition periods (65, 66).

As the first anti-CD3 monoclonal antibody approved for kidney transplantation, Muromonab (OKT3) significantly reduces acute cellular rejection risk by blocking T-cell receptor complex signaling. Early clinical trials demonstrated that sequential OKT3 therapy in KT and LT recipients achieved lower rates of biopsy-confirmed AR than did conventional triple therapy (prednisone + azathioprine + cyclosporine) (22% vs. 35%). However, the limited efficacy of OKT3 in heart transplantation may be attributed to distinct lymphocyte infiltration patterns within myocardial tissues (67–70). This study revealed that OKT3 was associated with decreased AR risks in LT, HT, KT, and PK transplant, while increased AR risk in IT recipients. This suggests that the same agent may exert opposing effects on AR across different organ transplant populations, a disparity potentially stemming from heterogeneity in T-cell thymic export dynamics and their differential responsiveness to CD3-targeted immunotherapy.

Polyclonal antibody agents exhibit marked variability in efficacy across different transplant types. For example, rabbit-derived antithymocyte globulin (ATG) showed significant advantages in heart transplantation, with recipients achieving a 1-year graft survival rate of 87% (vs. 79% in the IL-2R antagonist group). ATG significantly reduced the incidence of chronic allograft vasculopathy by modulating the regulatory T cell (Treg)/T helper 17 (Th17) balance (71, 72). In this study, the use of ATG (Atgam) in lung transplant recipients was associated with significantly improved survival rates, possibly by maintaining the innate immune balance in the lungs. Similarly, anti-lymphocyte globulin (ALG) showed a protective effect in liver transplantation, correlating with significantly improved recipient survival, which may be related to the synergistic effect of classic immunosuppressive regimens.

Cyclophosphamide (Cytoxan) serves as salvage therapy for refractory AR in liver transplantation, potentially increasing short-term graft survival through increased immunosuppression. However, in heart transplantation, evidence of its efficacy remains limited, with no significant reduction in rejection risk or improvement in patient survival (73).

The mechanisms by which cyclophosphamide induces immune tolerance primarily include (1) selective depletion of activated alloreactive T cells, thereby attenuating donor-specific immune attacks; (2) a reduction in the alloreactive T-cell repertoire via peripheral clonal deletion rather than intrathymic mechanisms; and (3) potential indirect enhancement of Treg functionality through immune microenvironment modulation, although further validation of its role in heart transplantation is required (74–77).

Further in-depth investigations into the precise mechanisms of action and therapeutic efficacy across different transplant types are required to elucidate the underlying pathways and clinical applicability. Such studies are crucial for guiding evidence-based clinical practice, optimizing immunosuppressive protocols, minimizing rejection episodes, and ultimately improving transplant recipients’ outcomes.

Belatacept (Nulojix) is a fusion protein composed of the Fc fragment of human IgG1 linked to the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), which selectively inhibits T-cell activation by blocking the CD28-B7 costimulatory pathway (78). Although Belatacept (Nulojix) can have a certain effect on the immune rejection response in SOT patients, its side effects and pharmacokinetic factors may not have a significant positive impact on the prognosis of SOT patients. Researches show that Belatacept (Nulojix) is associated with adverse effects including anemia, leukopenia, hypertension, and infection risks (e.g., urinary tract infections and respiratory tract infections) (79). In this study, belatacept (Nulojix) was associated with reduced patient survival rates in lung transplantation and simultaneous pancreas-kidney transplantation. As this study did not conduct subgroup analyses on the rejection risk of belatacept, the optimization of its immunosuppressive efficacy requires further exploration in future prospective studies.

Although this study offers important insights, there are a few limitations that should be noted. First, our research may have limited our knowledge of holistic treatment methods since it was primarily concerned with comparing individual immunosuppressants rather than thoroughly evaluating the possible advantages of combination therapy. Furthermore, the retrospective methodology limited a thorough understanding of the etiology of rejection by preventing a thorough investigation of the pathophysiological pathways driving immune rejection. Last but not least, immunosuppressants were roughly classified as “used” or “not used,” without considering precise timing, duration, or dose modifications—factors that might have a substantial impact on effectiveness and safety results.

Immunosuppressants play a crucial role in solid organ transplantation, but long-term use carries safety risks, mainly including increased incidence of infections and tumors. Immunosuppression reduces the body’s defense, significantly increasing the risk of bacterial, viral, and fungal infections, with respiratory infections being particularly common. During the COVID-19 pandemic, the severity of infections and hospitalization rates among immunosuppressed patients were higher than those in the general population. Specific drugs such as mycophenolate are associated with higher infection risks, indicating that the safety profiles of different drugs vary. Furthermore, long-term immunosuppression is closely linked to the development of malignant tumors, with transplant recipients having a significantly increased risk of skin cancer, mainly due to impaired immune surveillance. At the same time, immunosuppressants promote tumor progression by altering the tumor microenvironment, making tumor risk a long-term management challenge that requires careful balancing of treatment based on individual patient conditions (80). Currently, most studies are retrospective, lacking long-term follow-up and comparisons of risks among different drugs. Future research should conduct prospective multicenter studies to clarify the safety mechanisms, balance efficacy with risks. Meanwhile, exploring local drug delivery and personalized immunosuppression strategies can help reduce systemic side effects and improve patient outcomes (81). In addition, although the SRTR database used in this study covers a large amount of clinical data on transplant patients, data missingness and incompleteness are common throughout the database. Some key variables have a high rate of missing data, posing significant challenges for data cleaning and subsequent statistical analysis. Despite our implementation of a rigorous data processing workflow and multiple validation methods to minimize data bias, data missingness may still have some impact on the robustness and representativeness of the results. Therefore, the study conclusions should be interpreted with caution in light of this limitation. Future research should focus on optimizing data collection and quality control to enhance the completeness and applicability of the database. In conclusion, the long-term safety of immunosuppressants, especially in infection prevention and tumor monitoring, still requires in-depth research to optimize the long-term survival and quality of life for transplant recipients.

Our comprehensive analysis of the SRTR database reveals that acute rejection (AR) consistently impairs survival across all solid organ transplant types, underscoring the critical need for vigilant monitoring and prevention strategies. Immunosuppressants demonstrate organ-specific and formulation-dependent effects on AR risk and patient outcomes, with originator drugs often conferring superior protection (e.g., reduced AR odds with originator tacrolimus in lung transplantation) compared to generics, which may elevate risks in certain contexts (e.g., increased mortality with generic cyclosporine in heart transplantation). These findings advocate for personalized immunosuppression regimens, integrating transplant type, patient comorbidities, and drug bioavailability considerations to optimize long-term survival. From a policy perspective, our results highlight the importance of evidence-based guidelines for medical insurance coverage. Prioritizing originator immunosuppressants in high-risk scenarios—such as heart or lung transplants—could mitigate AR and improve outcomes, potentially reducing downstream healthcare costs from rejection episodes and retransplantation. Conversely, generics may be suitable for stable, low-risk patients (e.g., certain kidney transplants) to enhance affordability without compromising efficacy. Regulatory bodies and payers should incorporate such organ-specific data into reimbursement policies, fostering equitable access while balancing cost-effectiveness. Ultimately, this study informs multidisciplinary approaches to transplantation, promoting precision medicine and public health equity in organ recipient care.