2.1 Immune-mediated complications

Posttransplant immune-mediated complications, primarily consisting of rejection and graft-versus-host disease (GVHD), pose a significant challenge in the field of organ transplantation. Despite substantial progress in immunosuppressive therapy, rejection and GVHD continue to be critical factors impacting long-term graft and patient survival.

Rejection can occur in nearly all types of allogeneic organ transplantation. Based on the onset timing and underlying mechanisms, rejection can be classified as hyperacute, acute, or chronic.¹⁵ Hyperacute rejection typically manifests within minutes to hours posttransplantation and is primarily mediated by preexisting donor-specific antibodies, such as those encountered in ABO blood group-incompatible kidney transplantation.¹⁶ Acute rejection most commonly develops days to weeks posttransplantation and is characterized by a cytotoxic response driven by donor-specific lymphocytes, accompanied by humoral immune responses. Although the incidence of acute rejection following kidney and other organ transplantation has been markedly reduced with the use of immunosuppressive agents, the resulting graft damage and delayed graft function (DGF) continue to jeopardize recipient outcomes.¹⁷ Chronic rejection, occurring months to years posttransplantation, is a progressive pathological process characterized by graft vasculopathy and interstitial fibrosis. In solid organ transplantation (SOT), such as heart and other organs, these pathological changes can manifest early and exhibit a high incidence in the late posttransplant period. For instance, within 1 year following kidney transplantation, over 81% of patients develop interstitial fibrosis and tubular atrophy lesions stemming from cellular arteritis, with these lesions progressing to severe damage in more than 50% of transplanted kidneys within 5 years.¹⁸

GVHD is one of the most prevalent and severe complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT), frequently occurring in cases of incomplete donor–recipient (D–R) human leukocyte antigen (HLA) matching. Consequent to this histocompatibility disparity, immunocompetent cells within the graft mount an attack against recipient tissues, leading to dysregulation and dysfunction.¹⁹ Based on the onset timing and clinical manifestations, GVHD can be classified into two forms: acute and chronic. Acute GVHD typically manifests within 100 days posttransplantation, primarily affecting the skin, liver, and gastrointestinal tract. In contrast, chronic GVHD usually develops beyond 100 days posttransplantation and can involve any organ system.²⁰ Research indicates that the incidence of acute GVHD ranges from 28 to 40% in moderate-to-severe cases, while chronic GVHD can affect up to 70% of patients.^{21, 22} As one of the primary factors influencing allo-HSCT outcomes, GVHD is associated with a mortality rate of up to 25% in patients with chronic GVHD.²³ Despite the implementation of various preventive and therapeutic approaches, including immunosuppressive agents and cellular therapies, GVHD continues to pose a significant challenge in the context of allo-HSCT.

2.2 Infectious complication

Posttransplant infections contribute significantly to morbidity and mortality among transplant recipients. Approximately 70% of kidney transplant recipients are estimated to develop an infection within 3 years posttransplantation.²⁴ Following cardiovascular disease, infections are the second most common cause of mortality in transplant recipients. In the late posttransplant period (4–10 years), infections are the primary cause of mortality, particularly among diabetic patients.²⁵ Immunosuppressive therapy, administered to prevent rejection, increases the risk of infections in transplant recipients, primarily including donor-derived infections, nosocomial and community-acquired infections, and reactivation of latent pathogens.²⁶ Frequently encountered bacterial infections comprise those caused by gram-negative bacteria, such as Escherichia coli and Klebsiella pneumoniae, and gram-positive bacteria, including staphylococci and enterococci. These infections can affect various organ systems and are strongly associated with the type of transplanted organ. For instance, urinary tract infections are linked to kidney transplantation, intra-abdominal infections to liver transplantation, and pneumonia to lung transplantation.²⁷ Cytomegalovirus (CMV) is the most prevalent viral infection following transplantation, potentially leading to fever, leukopenia, and organ involvement.²⁸ Epstein–Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), human herpesviruses (HHVs), and other human viruses are frequently encountered viruses in the posttransplantation period. In addition to the aforementioned viruses, human herpesvirus (HHV)-6 and BK virus can also cause infections in transplant recipients.²⁹ In general, Pneumocystis jirovecii pneumonia and candidiasis are prevalent fungal infections following transplantation, whereas SOT recipients infected with invasive fungi, such as Aspergillus and Mucorales species, experience higher morbidity and mortality rates.^{30, 31} The incidence of posttransplant infections exhibits a distinct temporal pattern. In the first month posttransplantation, infections are commonly associated with surgical complications, nosocomial exposures, and donor-derived pathogens, including multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, carbapenem-resistant Enterobacteriaceae, and Clostridioides difficile. Opportunistic infections are more prevalent between 1 and 6 months posttransplantation, coinciding with the period of more intensive immunosuppression. During this time, reactivation of latent pathogens, such as BK virus, hepatitis C virus (HCV), and Mycobacterium tuberculosis, may also occur. Pneumocystis jirovecii pneumonia, herpesvirus infections (including CMV, HSV, VZV, and EBV), and hepatitis B virus (HBV) infections are less common during this period due to the use of prophylactic medications. Beyond 6 months posttransplantation, the majority of patients are on lower levels of immunosuppression, and infections are primarily community acquired. Moreover, there remains a risk of recurrent infections and delayed-onset viral infections, particularly CMV.^{32, 33} Consequently, pretransplantation screening of donors and recipients, immunization, optimal antimicrobial and antiviral prophylaxis, and prudent use of antibiotics can mitigate the impact of infections. Furthermore, screening donors for bacterial infections, such as urinary tract infections and bacteremia, is essential.

2.3 Metabolic and cardiovascular complications

Posttransplant diabetes mellitus (PTDM) is a prevalent endocrine metabolic disorder following SOT in adults, affecting 10% to 40% of recipients. New-onset diabetes after transplantation (NODAT), defined as diabetes that develops posttransplantation in patients without a prior history of diabetes, is a common and severe complication following transplantation of the kidney, liver, heart, and various other organs.³⁴ NODAT-related complications develop more rapidly compared with those in the general population with type 2 diabetes. Moreover, NODAT is associated with poorer outcomes, including an elevated risk of major cardiovascular events, graft failure, and mortality.³⁵ The primary pathogenic mechanism underlying NODAT is believed to be β-cell dysfunction. Other pathophysiologic processes involved in NODAT development include impaired insulin sensitivity and uncontrolled glucagon release.^36-39 Notable risk factors for NODAT include advanced age and obesity.^{40, 41} Importantly, the use of posttransplant immunosuppressive agents, such as glucocorticoids, calcineurin inhibitors (CNIs), and mammalian target of rapamycin (mTOR) inhibitors, is strongly associated with the development of NODAT.^{42, 43}

Dyslipidemia and hypertension are prevalent metabolic complications among various solid organ transplant recipients. Dyslipidemia, encompassing both hyperlipidemia and hypercholesterolemia, exhibits a high incidence following renal, hepatic, and cardiac transplantation.^44-46 In addition to nonmodifiable risk factors, such as advanced age and genetic predisposition, the use of immunosuppressive agents, including corticosteroids, CNIs, and mTOR inhibitors, are significant potential contributors to posttransplant dyslipidemia.⁴⁷ Hypertension is one of the most frequent cardiovascular complications following renal, cardiac, and pulmonary SOT.^48-50 The presence of common risk factors for hypertension in recipients, such as alcohol abuse, smoking, and obesity, along with transplant renal artery stenosis, allograft rejection, and immunosuppression, are contributing factors to posttransplant hypertension.^51-53 Notably, considering the substantial cardiovascular damage caused by dyslipidemia and hypertension, the management of blood lipids and blood pressure is crucial, particularly in heart transplant recipients.^{54, 55}

Cardiovascular disease is the primary cause of mortality in early SOT recipients.⁵⁶ The risk of cardiovascular complications, such as coronary artery disease, heart failure, arrhythmias, and pulmonary hypertension, is substantially higher in the transplant population compared with the general population.⁵¹ Moreover, factors such as smoking and obesity are also prevalent risk factors for posttransplant cardiovascular disease.⁵⁷ Notably, the aforementioned conditions, including diabetes, hyperlipidemia, hypertension, and the closely associated use of immunosuppressive agents, are all regarded as risk factors for the development of posttransplant cardiovascular disease.⁵⁸

2.4 Malignant cancer

Posttransplantation malignancies are among the most common postoperative complications in SOT and HSCT recipients, with an overall prevalence ranging from 4 to 18%.¹ High-risk types of de ^{novo posttransplant malignancies} include skin cancer, genitourinary cancers, and posttransplant lymphoproliferative disease (PTLD).⁵⁹ In addition to traditional risk factors, such as smoking, sun exposure, and family history of cancer, the transplant population has unique risk factors for malignancy, including immunosuppression, oncogenic viruses, and donor-derived transmission.⁶⁰ Epidemiologic data demonstrate that the incidence of de novo malignancies within 10 years posttransplantation is two to three times higher in transplant recipients compared with the general population, with the incidence of nonmelanoma skin cancers being up to 13 times higher than in the nontransplant population.⁶¹ In general, the prognosis of de novo malignancies following transplantation is poor, with the 5-year survival rate being substantially lower compared with patients with similar malignancies in the general population. At present, malignancies have become a leading cause of long-term mortality in transplant recipients, necessitating close follow-up, and surveillance.

In addition to novo neoplastic malignancies, virus-associated cancers constitute a significant category of posttransplantation malignancies. Frequent viral infection-associated posttransplantation malignancies include EBV-associated PTLD, HHV-8-associated Kaposi's sarcoma (KS), and human papillomavirus-associated skin cancer, anogenital cancer, and head and neck cancer.^62-64 Among these, PTLD, one of the most common posttransplantation malignancies, is associated with EBV infection in approximately 55−65% of cases.^{65, 66} Upon entering the human body, EBV typically first infects the oropharyngeal epithelial cells. As the viral infection subsides, the small amount of EBV present in B cells enters a latent period, evading the host immune system. Following reactivation of the virus due to various factors, the lifespan of the virus-infected B lymphocytes is prolonged, with an increased potential for mutations.^{65, 67, 68} Patients with early-onset PTLD are typically EBV-positive and have a remarkably high mortality rate.^{69, 70} Moreover, HHV-8-associated virologic markers are positive in nearly all transplant recipients with KS.⁶⁴ KS in the immunosuppressed state is typically more aggressive and fatal compared with immunocompetent recipients.⁷¹ Notably, all malignancies with a substantially increased risk compared with the general population were associated with viruses, underscoring the crucial role of oncogenic viruses in posttransplant cancers.⁶⁰

2.5 Other complications

DGF is one of the most common early complications following kidney transplantation, with an incidence of approximately 25−30%.⁷² Although there are various definitions of DGF, the most widely accepted one is the failure of the transplanted kidney to function at the expected level within 7 days posttransplantation, often necessitating dialysis.⁷³ The occurrence of DGF is closely associated with donor factors (e.g., advanced age, deceased donor transplantation), recipient factors (e.g., immune hyperreactivity, recurrence of kidney disease), and perioperative factors (e.g., ischemia–reperfusion injury, immunosuppressant toxicity).⁷⁴ Notably, both acute and chronic rejection are important causes of DGF exacerbation, which significantly reduces posttransplant survival.⁷⁵ Substantial clinical evidence demonstrates a strong association between DGF and subsequent chronic allograft dysfunction.^{76, 77}

Transplant recipients frequently experience a range of comorbid gastrointestinal and neurologic complications. Gastrointestinal symptoms, including nausea, vomiting, and diarrhea, may be associated with factors such as immunosuppressant medications (e.g., mycophenolate mofetil [MMF]) and infections (e.g., CMV enteritis).^{78, 79} Moreover, transplant recipients have an increased risk of developing severe gastrointestinal complications, such as diverticulitis and gastrointestinal perforation.^{80, 81} Targeted modification of immunosuppressive regimens, prevention and treatment of related infections, and symptomatic supportive care are essential for managing posttransplant gastrointestinal complications.⁸² Neurologic complications, such as headache, tremor, and sensory abnormalities, may be associated with immunosuppressant neurotoxicity (e.g., tacrolimus), infections (e.g., cryptococcal meningitis), and metabolic disturbances (e.g., hypomagnesemia).^{83, 84}

3.1 Posttransplant complications due to overimmunosuppression

SOT and allo-HSCT are crucial clinical treatments for numerous end-stage diseases. However, the posttransplantation period is frequently characterized by severe immune complications, primarily manifested as allograft rejection and GVHD. Although the contexts of occurrence and clinical manifestations of these two complications differ, the underlying immune activation and effector mechanisms share substantial similarities. This section will systematically summarize and discuss the mechanisms underlying these two types of complications (Figure 1).

3.2 Posttransplant complications due to under-immunosuppression

Immunosuppressive therapies play a crucial role in transplantation antirejection therapy; however, they can also cause severe adverse reactions through various pathways. A comprehensive understanding of the mechanisms of action of immunosuppressive therapies is essential for optimizing immunosuppressive regimens and minimizing the risk of complications. This section will explore the molecular mechanisms underlying the heightened susceptibility to infections and increased risk of tumorigenesis associated with immunosuppressive therapies (Table 1 and Figure 2).

3.3 Metabolic and cardiovascular complication

Metabolic and cardiovascular complications are significant concerns in the posttransplant period, substantially impacting patient outcomes and quality of life. These complications arise from a complex interplay of factors, including the effects of immunosuppressive medications, infections, and the underlying health conditions of transplant recipients. Understanding the mechanisms behind these complications is crucial for developing effective prevention and treatment strategies. This section will explore two major contributors to posttransplant metabolic and cardiovascular complications: drug-induced metabolic disorders and toxicity, and the critical role of infections.

4.1 Immunosuppressive therapies and novel cellular therapies

To prevent rejection or GVHD associated with transplantation and to induce tolerance, immunosuppressive therapies are now widely used in posttransplantation patients. The three-signal model of T-cell activation and proliferation provides a basis for understanding the molecular mechanisms of immunosuppression.²²⁰ In this model, signal 1 is the presentation of foreign antigen by APCs to T cells, activation of their TCR, and signaling through the transduction apparatus of the CD3 complex. Signal 2 is an antigen-nonspecific costimulatory signal that results from the interaction of multiple ligand molecules on the surface of the APC with multiple receptors on the surface of the T cell, such as CD28 and CD154. Both signal 1 and signal 2 activate signal transduction pathways, including the calcium–calmodulin-dependent phosphatase pathway, the mitogen-activated protein kinase pathway, and the NF-κB pathway. Signal 3 refers to the stimulation of the cell cycle by increased production of IL-2 through the IL-2 receptor. This process requires the mTOR enzyme to translate mRNA translation and cell proliferation.^{221, 222}

Immunosuppressive therapy is primarily divided into induction therapy and maintenance therapy, based on the different treatment objectives.²²³ Induction therapy primarily aims to rapidly and potently suppress the body's immune response in the short term before and after transplantation surgery to prevent the occurrence of acute rejection. It mainly includes various antibodies. These antibodies have different mechanisms of action, depending on their target. For example, belatacept blocks the interaction of APCs with CD28 molecules on T lymphocytes, thereby blocking signal 2.²²⁴ IL-2 receptor antagonists, such as basiliximab, inhibit lymphocyte activation and replication, thereby blocking signal 3.²²⁵ Moreover, polyclonal antibodies, such as antithymocyte globulin, can recognize multiple markers and exhibit a broad immunosuppressive profile.²²⁴ Maintenance therapy aims to control chronic graft rejection and maintain stable graft survival in the long term. Commonly used drugs include CNIs, antimetabolites, mTOR inhibitors, and glucocorticoids. CNIs, including cyclosporine A and tacrolimus, primarily exert their immunosuppressive effects by inhibiting calcineurin.²²⁶ mTOR inhibitors, such as sirolimus and everolimus, exert their immunosuppressive effects by inhibiting the proliferation and differentiation of T cells and B cells, as well as antibody production.^{227, 228} Antimetabolites, such as azathioprine and MMF, inhibit lymphocyte proliferation by inhibiting nucleic acid synthesis.^{222, 224} Glucocorticoids, such as methylprednisolone and prednisone, exert immunosuppressive and anti-inflammatory effects.²²⁹ It is crucial to note that these immunosuppressive regimens are based on appropriate combinations of drugs with different mechanisms of action and need to be tailored to the individual patient. Currently, a commonly used regimen is based on triple drug therapy containing CNIs, corticosteroids, and antimetabolites.²²³

Considering the immunocompromise and toxicity inevitably associated with immunosuppressants, cellular therapy, particularly Treg-based therapy, is of great importance in reducing the use of immunosuppressive therapy in patients. Currently, several clinical trials have demonstrated that Treg cell therapy has shown promising results in renal, hepatic, and other SOT patients.^230-234 For example, the results of the study by Sawitzki et al.²³² (The ONE Study) showed that it is feasible and safe for living kidney transplant recipients to receive Treg cell therapy with a relatively lower risk of infection. Additionally, a study by Todo et al.²³⁴ demonstrated that living liver transplant recipients who received Treg therapy to induce immune tolerance had 7 out of 10 patients maintaining immunosuppression-free status for more than 6 years. The safety and efficacy of this therapy need to be further confirmed by additional studies.

4.2 Prevention and treatment of infections

The prevention of common infections in transplant recipients requires a multifaceted and comprehensive approach. On the one hand, comprehensive pretransplant screening of donors and recipients for infectious diseases is crucial. According to the recommendations in the American Society of Transplantation Clinical Practice Guidelines, transplant recipients should be screened preoperatively for various pathogens, including human immunodeficiency virus (HIV), tuberculosis, CMV, influenza, and pneumococcus. Moreover, in patients with active or recent peritonitis, it is recommended to delay transplantation to minimize the risk of infection.²³⁵ On the other hand, the guidelines also recommend immunization of transplant recipients well before transplantation, including pneumococcal, measles, mumps, rubella, diphtheria, tetanus, and pertussis vaccines.²³⁵ Furthermore, the resumption of vaccinations should be delayed after transplantation until immunosuppression is minimized and the vaccine's efficacy is serologically confirmed.²³⁶ Additionally, the importance of preoperative prophylactic medication against the risk of infection should be emphasized. For instance, in transplant recipients at high risk of CMV infection, preoperative oral ganciclovir is beneficial for graft survival.²³⁷ For donors, screening of donor organs for HBV, HCV, HIV, tuberculosis, schistosomiasis, and other infections should be emphasized to prevent the transmission of latent infections from the donor through infected organs.^{238, 239}

When posttransplantation infection occurs, the timely selection of the appropriate treatment regimen and continuous monitoring are crucial. On the one hand, appropriately reducing the use of immunosuppressants is beneficial for the recovery of the body's ability to fight infection and improves therapeutic efficacy. For instance, in patients with EBV-associated PTLD, reducing the use of immunosuppressants can lead to remission in 23−86% of patients.²⁴⁰ On the other hand, it is crucial to select the appropriate highly effective drugs for treatment based on the infecting pathogen. For viral infections, ganciclovir/valganciclovir for CMV, rituximab for EBV-associated PTLD, and tenofovir or entecavir for HBV have shown promising results.^33-241-242 For HIV infection or bacterial infections, the appropriate antibiotics should be chosen to prevent or control the infection. Furthermore, active tuberculosis requires a 6-month treatment regimen with isoniazid, rifampicin, pyrazinamide, and ethambutol, using all four drugs for the first 2 months and isoniazid and rifampicin for the remaining 4 months.²⁴³

4.3 Metabolic and cardiovascular risk management

The treatment of patients with PTDM should be chosen according to different stages. Intravenous insulin infusion is usually used in the early postoperative stage, followed by a transition to subcutaneous insulin injections. For long-term glycemic management of PTDM, long-term insulin use is also crucial.⁷ Additionally, common posttransplant oral hypoglycemic agents include metformin, sulfonylureas, and repaglinide.^244-246 Among these, metformin has many advantages as a potential first-line agent for posttransplant PTDM.²⁴⁷ Shivaswamy et al.²⁴⁸ demonstrated that in rats, metformin tended to reduce tacrolimus/sirolimus treatment-induced endocrine cell apoptosis and ameliorate hyperglycemia induced by these immunosuppressive agents. Moreover, several studies have not observed any impairment or significant side effects of metformin on long-term graft survival, suggesting its relative safety.^{249, 250} For patients with posttransplant dyslipidemia, statins are effective in lowering LDL levels and are recommended as the first-line treatment and drug of choice for posttransplant dyslipidemia.^178-251 It is worth noting that statins are also believed to improve endothelial function, thereby benefiting cardiovascular health.²⁵² Furthermore, drugs such as fibrates, niacin, and HMG-CoA reductase inhibitors have shown promising therapeutic effects on posttransplant dyslipidemia due to their ability to LDL cholesterol levels.^178-253 Calcium channel blockers, which antagonize the vasoconstrictive effects of CNIs with fewer side effects, are considered first-line agents in the management of posttransplant hypertension.^182-254 Moreover, thiazide diuretics have demonstrated antihypertensive efficacy and safety in posttransplant hypertension.²⁵⁵ For posttransplant cardiovascular disease, it is crucial to manage the aforementioned metabolic complications.⁵⁶ Notably, for metabolic complications and cardiovascular disease, lifestyle modifications such as smoking cessation and exercise are essential for prevention and improving prognosis.^{256, 257}

For many transplant-related metabolic and cardiovascular diseases, it is crucial to minimize the potential risk of complications associated with immunosuppressive therapy. In fact, several immunosuppressive agents have a relatively lower risk of complications and are considered more favorable options. A 12-month, multicenter, prospective, randomized controlled trial by Wissing et al.²⁵⁸ found that therapeutic switching from tacrolimus to cyclosporine A significantly improved glucose metabolism in renal transplant recipients postoperatively and had the potential to reverse PTDM in the first year after transplantation. A randomized controlled trial by Kim et al.²⁵⁹ demonstrated that everolimus exhibited lower insulin resistance compared with low-dose tacrolimus. Moreover, a study by Wen et al.²⁶⁰ demonstrated that the costimulation blocker belatacept, alone or in combination with tacrolimus, had a lower risk of PTDM compared with tacrolimus alone. However, the effect of tacrolimus on posttransplant hyperlipidemia was less pronounced than that of cyclosporine, and replacing cyclosporine with tacrolimus led to a 25% reduction in LDL cholesterol.²⁶¹ Moreover, numerous studies have shown that the use of belatacept, either without or with reduced CNI exposure, can lower posttransplant lipid levels.^{262, 263} In patients with posttransplant hypertension, tapering, discontinuing, or avoiding corticosteroids and CNIs in favor of belatacept or mTOR inhibitors can be effective in controlling blood pressure.^262-264-265 Considering the significance of each metabolic complication in the development of cardiovascular disease, the impact of these immunosuppressive regimen changes on cardiovascular disease risk has also garnered considerable research attention. For instance, Vincenti et al.²⁶⁶ found a lower risk of serious cardiac events compared with cyclosporine by evaluating the long-term safety profile of belatacept over a 5-year period. Table 2 summarized the therapeutic interventions and management strategies in posttransplant complications.

4.4 Diagnosis and treatment of posttransplantation cancers

The high incidence and poor prognosis of posttransplant cancers underscore the importance of screening and early detection. Individualized cancer screening protocols for transplant recipients can help identify and intervene in cancers as early as possible, thereby improving prognosis. Considering that immune disorders are critical for posttransplantation tumorigenesis, the potential value of ILs as diagnostic markers for posttransplantation cancers has garnered considerable attention. Pontrelli et al.²⁶⁷ identified differentially expressed genes in patients with and without posttransplantation malignancies. The results showed that these differentially expressed genes were closely associated with the cancer pathway and that the IL-27-related genes were the most downregulated.²⁶⁷ Zhang et al.²⁶⁸ demonstrated that, compared with primary cutaneous squamous cell carcinoma (SCC), the number of IL-22-secreting CD8+ T cells in skin SCC tissues after skin transplantation was higher, and the expression of IL-22 receptor in tissues was more diffuse. Furthermore, they found that increased IL-22 and IL-22R expression accelerated tumor growth in transplant patients.²⁶⁸ Moreover, T-lymphocyte-associated cell surface markers demonstrated promising predictive value. CD200, a membrane protein with immunosuppressive function expressed in hematopoietic tumors, suppresses the body's antitumor immunity by binding to the receptor CD200R, inducing Treg expression, and inhibiting tumor-specific T-cell function.^269-271 The study by Vaughan et al.²⁷² suggests the potential value of CD200 in posttransplantation cancers. Their study showed that 23.7% (nine out of 38) of PTLD patients exhibited CD200 positivity and that tumor cells exhibited membrane and cytoplasmic CD200 positivity. Furthermore, they found that PTLD patients with CD200 positivity had higher levels of Tregs compared with those with CD200 negativity.²⁷² CD57 is a marker expressed on highly differentiated T cells, and an increased frequency of CD57-positive T cells has been associated with various cancers. The reduced proliferative capacity of these cells suggests that the organism is in a state of chronic immune activation and senescence.^{273, 274} Bottomley et al.²⁷⁵ demonstrated that in kidney transplant recipients with cutaneous SCC, participants who highly expressed CD57 were more likely to develop SCC during follow-up and tended to develop and experience recurrence earlier. They concluded that the percentage of CD8+ T cells expressing CD57 is a robust immune predictor of SCC occurrence and recurrence in long-term, high-risk kidney transplant recipients.²⁷⁵ Courivaud et al.²⁷⁶ found that CMV-exposed renal transplant recipients were found to have a higher cumulative incidence of tumors compared with the unexposed population and a relatively shorter mean time to tumor onset. Notably, their results also demonstrated that CD57-depleted T cells were significantly expanded in CMV-exposed patients.²⁷⁶ Collectively, these studies suggest the potential significance of CD57 in predicting posttransplantation cancers. Moreover, the efficacy of EBV DNA for the diagnosis of PTLD has been widely recognized as a risk factor for the development of PTLD.²⁷⁷ A study by Rosselet et al.²⁷⁸ demonstrated that in seven out of 10 EBV-positive PTLD patients, serum EBV DNA levels could be monitored in five of them. In contrast, EBV DNA was not detected in any of the 38 control subjects. Furthermore, a study by Suresh et al.²⁷⁹ demonstrated that in pediatric renal transplant recipients, an acute elevation of urinary CXCL10/creatinine ratio was associated with the development of transplant-associated Burkitt's lymphoma, suggesting its potential value as a diagnostic biomarker.

Targeting the mechanisms of posttransplantation cancer development and progression is crucial for prevention and treatment. For example, sirolimus, which can reduce the activating effect of IL-2 on T cells by inhibiting the mTOR receptor, has been used for immunosuppression in transplantation medicine, particularly after renal transplantation.^{280, 281} Notably, despite their immunosuppressive effects, some mTOR inhibitors can also suppress posttransplant tumorigenesis under certain circumstances.²⁸² A randomized controlled trial by Knoll et al.²⁸³ demonstrated that a combination regimen was associated with a reduced risk of malignant tumors and nonmelanoma skin cancers in transplant recipients, compared with an immunosuppressive regimen without sirolimus. A meta-analysis by Yanik et al.²⁸⁴ revealed that sirolimus use in renal transplant recipients was associated with a lower risk of renal carcinogenesis. Considering the central role of the PI3K/Akt/mTOR pathway in the growth, proliferation, and other functions of cancer cells, this may be a potential mechanism by which mTOR inhibitors suppress tumorigenesis after transplantation.²⁸⁵ Given the dual role of mTOR inhibitors in suppressing posttransplantation rejection and reducing the risk of posttransplantation tumorigenesis, they are essential for the prevention and treatment of specific types of posttransplantation cancers. Moreover, targeted therapies aimed at inhibiting Tregs in the management of posttransplantation tumors have garnered significant interest. Numerous studies have investigated the potential efficacy of ipilimumab (anti-CTLA-4), basiliximab (anti-CD25), and denileukin diftitox in depleting intratumoral Tregs.^286-289 Similarly, targeting the chemokine receptor CCR8 to inhibit Tregs has gained traction in recent years, as it is believed to facilitate dose-dependent, potent, and long-lasting antitumor immune responses.²⁹⁰ Furthermore, targeted therapies directed against the transcription factor Foxp3, such as TCR mimetic antibodies that selectively bind to Foxp3-expressing Tregs, have demonstrated considerable promise in Treg depletion.²⁹¹ At present, these Treg depletion strategies have exhibited favorable antitumor effects in various malignancies, including gastric, head and neck, and lung cancers.^287-293 In the context of treating posttransplantation tumor recurrence following hematologic transplantation, several Treg depletion approaches have yielded promising outcomes.^288-294 For patients with recurrent multiple myeloma undergoing autologous stem cell transplantation (ASCT), two strategies—the elimination of Tregs in ASCT grafts using anti-CD25 microbeads and the in vivo depletion of Tregs using basiliximab—significantly reduced the frequency of Tregs post-ASCT.²⁸⁸ Among recipients of allo-HSCT, the inhibition of Tregs using antitumor necrosis factor receptor type 2 (TNFR2) therapy was demonstrated to elicit an allogeneic response and consequently induce substantial antitumor effects.²⁹⁴ Moreover, for patients with recurrent hematologic malignancies following allo-HSCT, ipilimumab has been shown to restore the body's antitumor responsiveness by enhancing the graft-versus-tumor effect.²⁹⁵ In summary, while additional studies and clinical validation are still required, the potential utility of Treg depletion strategies in managing posttransplantation tumors presents a promising therapeutic approach. The therapeutic potential of allogeneic cell therapy (ACT), including allogeneic T-cell therapy and antiviral ACT, has garnered significant attention. In SOT, such as kidney and heart transplantation, numerous case reports have indicated that chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated therapeutic efficacy in PTLD.^296-298 Moreover, evidence suggests that CAR-T therapy may also be effective in treating PTLD and drug-resistant or refractory PTLD after allo-HSCT.^{299, 300} Furthermore, a systematic evaluation study by Liu et al.³⁰¹ demonstrated that, in addition to post-HSCT PTLD, virus-specific CTLs targeting EBV (EBV-CTLs) exhibited safe therapeutic efficacy. Donor-derived CMV-specific CTLs (CMV-CTLs) reduce the severity of CMV infection after transplantation, which may increase the risk of tumorigenesis in renal transplant recipients.^{302, 303} Moreover, Blyth et al.³⁰⁴ observed that donor-derived CMV-CTLs reduced the need for CMV-directed drug therapy in allogeneic stem cell transplant recipients. Figure 3 summarized the diagnostic and therapeutic strategies for posttransplant cancers. Additionally, Table 3 compiles recent preclinical and clinical studies on the treatment of posttransplant complications from the past five years.

4.5 Pharmacogenetics and immunogenetics in personalized immunosuppression and risk stratification

Pharmacogenetics and immunogenetics have emerged as critical areas of investigation in personalized medicine, particularly in the realm of immunosuppression management and risk stratification for transplant recipients. Currently, one of the most extensively studied pharmacogenetic markers is the cytochrome P450 3A5 (CYP3A5) polymorphism, which significantly influences the metabolism of tacrolimus, a widely used immunosuppressant in transplantation medicine. Individuals possessing a CYP3A5 expression genotype require a longer duration to achieve target tacrolimus plasma concentrations compared with nonexpressers.³³⁵ Given the pivotal role of immunosuppressants in posttransplantation complications, numerous studies are presently exploring the impact of CYP3A5 expression on the risk of such complications. Research conducted by Cheng et al.³³⁶ demonstrated that among renal transplant recipients receiving tacrolimus, patients with the CYP3A5*1*1 genotype necessitated higher drug doses to attain target plasma concentrations, potentially resulting in insufficient immunosuppression and consequently elevating the risk of acute rejection. Multiple studies have corroborated this increased rejection risk associated with the CYP3A5*1 allele.^{337, 338} Furthermore, among allo-HSCT recipients receiving tacrolimus, those expressing CYP3A5 exhibited a higher incidence of GVHD.³³⁹ These findings suggest that pretransplant administration of immunosuppressants based on genotypes of genes such as CYP3A5 may facilitate the achievement of desired therapeutic concentrations, thereby optimizing transplant outcomes and mitigating adverse effects associated with immune overactivation. Regarding immunogenetic markers, HLA typing remains a crucial factor in organ transplantation. Matching donor and recipient HLA alleles can significantly reduce the risk of graft rejection and improve long-term outcomes.³⁴⁰ The degree of HLA compatibility between donor and recipient is inversely correlated with the risk of rejection.³⁴¹ Consequently, adjusting the dosage of recipient immunosuppressants according to the degree of HLA matching may be advantageous in preventing immunosuppression-related complications, such as infections. It is noteworthy that a substantial body of research has demonstrated the critical importance of matching ABO blood group antigens and MHC class I polypeptide-related sequence A (MICA) between donor and recipient in controlling rejection.^{342, 343} Moreover, variations in genes encoding cytokines and their receptors have been associated with distinct immune responses, which may inform risk stratification and guide tailored immunosuppressive strategies.³⁴⁴ For instance, the study by Dukat-Mazurek et al.³⁴⁵ confirmed a potential correlation between acute GVHD following HSCT and IL-6 genotype C/C homozygosity. Additionally, they identified a significant protective effect of the IL-10 gene GCC/ATA haplotype on the development and severity of GVHD.³⁴⁵

5.1 The role of more immune cells in posttransplant complications

In the previous section, we discussed the pivotal roles of CD4+ and CD8+ T cells in posttransplant complications. However, the involvement of additional T cell subsets in the development of posttransplant complications remains unclear. Indeed, accumulating evidence suggests that other T cell subsets can be equally influential in the development of posttransplant complications.^{346, 347} Natural killer T (NKT) cells are a distinct class of innate T lymphocytes that recognize lipid antigens presented by the MHC class I molecule CD1d. During liver transplantation-associated infections with pathogens such as HBV or HCV, different NKT cell subtypes can eliminate infected cells and pathogens through direct cytotoxic effects and by promoting the activation of CTLs.^{348, 349} In antitumor immunity, NKT cells can sense tumor-mediated changes in lipid metabolism by recognizing endogenous lipids and modulate anticancer immunity by secreting a series of cytokines.³⁴⁶ Indeed, numerous studies have observed an association between transplantation-related factors and NKT cells.^{350, 351} Moiseev et al.³⁵⁰ demonstrated that higher levels of NKT cells in peripheral blood stem cell transplant donors were associated with impaired immune recovery in recipients treated with posttransplant cyclophosphamide. Furthermore, a study by Hodge et al.³⁵¹ revealed that immunosuppressants, such as cyclosporine and prednisolone, inhibited the production of proinflammatory cytokines, including IFN-γ and TNF-α, by NKT cells. In addition to NKT cells, the potential role of gamma delta (γδ) T cells in posttransplantation complications is also of interest. In many cases, γδ T cells can directly recognize antigens through their γδ TCR without the involvement of APCs.³⁵² In transplantation-associated complications, γδ T cells can play multiple roles. On the one hand, certain subsets of γδ T cells may suppress the immune function of transplant recipients.³⁵³ In hematopoietic stem cell transplantation, IL-17A-producing γδ T cells can effectively enhance immunosuppression.³⁵⁴ In liver transplant recipients, γδ T cells have also been reported to be associated with hepatic allograft tolerance. Therefore, these γδ T cell-associated immune impairments may increase the risk of posttransplant infections and tumorigenesis. On the other hand, in some cases, γδ T cells can control the reactivation of viruses, such as EBV and CMV, which may enhance their ability to achieve posttransplant tumor suppression.³⁵⁵ Currently, substantial evidence supports that transplantation-related factors, such as the use of immunosuppressants and CMV infection, have a significant effect on γδ T cells.^{347-355, 358} Therefore, the impact of γδ T cells on posttransplantation cancers cannot be overlooked. However, there is still a paucity of studies to elucidate the precise role of T cell subsets, such as NKT and γδ T cells, in posttransplant infections or tumors. Therefore, more refined phenotyping criteria for T cell subsets need to be further investigated.

In addition, the crosstalk between other immune cells and T cells in the onset of impaired immune surveillance after transplantation warrants further investigation. In addition to NK cells and γδ T cells, other innate lymphoid cell (ILC) subpopulations, such as group 2 ILCs (ILC2s) and group 3 ILCs (ILC3s), play an equally important role in posttransplantation immunity.³⁵⁷ ILC2s can promote antigen-specific CD4+ T cell responses through the expression of MHC class II molecules and enhance NK cell cytotoxicity and T cell responses by secreting IL-13.^{358, 359} On the other hand, ILC3s promote CD4+ and CD8+ T cell infiltration in tumors by producing CXCL10.³⁶⁰ Furthermore, tumor-associated macrophages (TAMs) also influence the antitumor immune function of T cells. Under specific circumstances, TAMs may inhibit CD8+ T cell recruitment by producing IL-15/IL-15 receptor alpha complexes while promoting Tregs by producing C-C motif chemokine ligand 22.^{361, 362} Currently, the impact of these cells on posttransplantation infections or tumorigenesis needs to be further elucidated. Furthermore, it is necessary to thoroughly investigate whether other cells can also influence T cells, leading to impaired immune surveillance after transplantation.

5.2 Emerging clinical diagnostic technologies

The potential application of additional bioinformatics techniques in the diagnosis of posttransplantation complications requires further investigation. Given the central role of T cells in transplantation-associated immunity, conventional techniques capable of identifying T cell-associated biomarkers, such as single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and mass cytometry by time-of-flight, have been extensively employed in the diagnosis of posttransplantation complications, such as cancers.^363-365 Recently, novel techniques have been employed to evaluate T cell function, such as TCR sequencing (TCR-seq) and peptide–MHC multimer technology.^366-368 These techniques have been applied to monitor posttransplant complications, such as the risk of immune rejection and T cell-mediated antitumor immune responses. However, their potential application in the diagnosis of other posttransplant complications requires urgent investigation.^369-371 Importantly, diagnosing posttransplantation complications from a multiomics perspective is a promising research avenue. The development of multiomics-based biomarkers for posttransplant rejection is currently a highly active area of research.³⁷² For instance, Lin and colleagues¹⁸⁷ developed a novel bioinformatics approach for identifying microRNA markers closely associated with kidney transplant rejection by integrating multiomics data to construct a molecular interactome network. Moreover, genomics, transcriptomics, and proteomics related to T cells have been extensively employed in detecting posttransplantation cancers.^373-376 Furthermore, other omics approaches have gained increasing attention, particularly metabolomics, which has potential diagnostic value for posttransplantation complications due to its ability to monitor T cell function.³⁷⁷ For example, measuring the levels of mitochondrial and lipid metabolism in Tregs can reflect anti-infective or antitumor immunity.³⁷⁸ Additionally, given the role of various viruses and bacteria in posttransplant infections and tumors, the value of microbiome analysis in this context has also garnered attention. For instance, a study by Tellez et al.³⁷⁹ demonstrated the reliability of microbial assay arrays in monitoring EBV infection in lymphoma. Although numerous studies suggest the potential value of multiomics approaches in diagnosing posttransplantation cancers, their application requires further investigation.

Interestingly, certain clinical diagnostic techniques focusing on T cells have potential applications in diagnosing posttransplant complications. Imaging is one such technique with potential applications in this context.¹⁰ For example, a study by Anthony et al.³⁸⁰ demonstrated that by injecting D-luciferin into mice after bone marrow transplantation and using bioluminescence imaging, researchers could track specific T cell subpopulations and hypothesize about their contribution to GVHD at different time points. Notably, this noninvasive technique for monitoring T cell activity may also show promise in posttransplant tumor surveillance.³⁸⁰ Similarly, pathological analyses targeting T cells also have potential applications in diagnosing posttransplantation tumors. In patients with posttransplantation tumors, Datta et al.¹ adequately assessed CD8+ T cell abundance in the tumor microenvironment by performing digital image analysis of tumor and adjacent tissue sections, finding that reduced abundance correlated with impaired cancer immune surveillance. Furthermore, Mohri et al.³⁸¹ used microscopy to observe the presence of numerous large atypical cells in the background of dense T cell aggregates, using this pathological feature as evidence to support the diagnosis of classical Hodgkin lymphoma-type posttransplant lymphoproliferative disorder following renal transplantation. In the future, it will be essential to investigate additional clinical diagnostic techniques focusing on T cells and explore their potential applications in diagnosing posttransplantation tumors.

5.3 Advancing personalized management with cutting-edge technologies

Multiomics technologies have demonstrated exceptional performance in the accurate and comprehensive prediction of posttransplant complications, which provide crucial guidance for improving transplant patient outcomes. In the field of genomics, Ma et al.³⁸² developed a 355-gene transplant incidence panel encompassing cardiovascular disease, immunodeficiency, malignancy, and thrombosis. Their evaluation of this genetic panel, using exome sequencing data from 1590 kidney transplant recipients, revealed that approximately 9% of patients harbored variants predisposing them to these complications. This finding underscores the potential value of genetic testing in informing clinical decision-making, such as implementing more intensive monitoring, adjusting immunosuppressive regimens, or initiating specialist referrals.³⁸² Proteomics has garnered significant attention in posttransplantation complication research. Hu et al.³⁸³ conducted antibody array analyses on urine samples from kidney transplant recipients, identifying significantly elevated levels of 11 cytokines/chemokines in patients experiencing acute rejection compared with healthy controls. Their study further demonstrated that a combination of markers, including 10 kDa induced protein, IFN-γ-induced monokine and macrophage inflammatory protein-1Delta, could differentiate between acute and chronic injury.³⁸³ Additionally, the application of other multiomics approaches, such as transcriptomics and metabolomics, in posttransplantation complication studies has gained increasing traction.^{384, 385} Systems biology adopts a holistic perspective, integrating multiomics data to generate and validate novel hypotheses regarding organ function and failure. This approach necessitates addressing data variability, noise, and scale, while combining experimental big data with computational models to reconstruct and elucidate biological processes.³⁸⁶ Sui et al.’s³⁸⁷ research exemplifies the potential of systems biology in posttransplantation complications. By integrating proteomics and genomics technologies, they explored the expression levels of transcription factors, microRNAs, and long noncoding RNAs in biopsy samples from kidney transplant patients with acute rejection and healthy controls, identifying characteristic markers through association analysis.³⁸⁷ Future research should focus on optimizing systems biology methods and integrating more multiomics data to develop accurate predictive models. These advancements aim to enable early detection and personalized treatment of posttransplantation complications, ultimately improving long-term patient outcomes. Machine learning (ML) further enhances personalized management by leveraging large-scale clinical and molecular data to identify patterns and predict outcomes with high accuracy. ML has been widely applied in D–R matching prediction prior to transplantation.^{388, 389} For instance, Briceño et al.³⁹⁰ employed artificial neural networks for D–R matching in liver transplantation, demonstrating superior performance in predicting graft survival and probability of graft loss compared with validated graft survival scores.³⁹¹ ML-based analyses hold promise for achieving precise D–R matching, potentially preventing posttransplantation complications. ML has also shown efficacy in predicting posttransplantation patient prognosis and exhibits significant potential in forecasting the risk of complications such as rejection, GVHD, and malignancy.^392-397 In many instances, ML demonstrates superior predictive capabilities compared with traditional methods. For example, Zare et al.³⁹⁸ reported that ML models outperformed conventional logistic regression in predicting acute rejection in liver transplant patients. Notably, ML techniques offer substantial advantages in processing unstructured data, such as medical imaging.³⁹⁹ In conclusion, advanced research methodologies including multiomics, systems biology, and ML are transforming the landscape of transplant medicine. These approaches are paving the way for more effective and personalized therapeutic interventions. The integrated application of these technologies is expected to significantly enhance the prevention, diagnosis, and treatment of posttransplantation complications, ultimately improving patients’ long-term quality of life.

5.4 Balance of GVHD and posttransplantation cancers

Finally, the question of how to combat posttransplant tumors without causing GVHD is also an urgent one. Although the immunosuppressive effects of mTOR inhibitors are thought to counteract their anticancer effects, a substantial body of research suggests that mTOR inhibitors have a facilitating effect on the anticancer function of CD8+ T cells.^{400, 401} A randomized controlled trial by Knoll et al.²⁸³ demonstrated that, compared with an immunosuppressive regimen without sirolimus, the combination regimen was associated with a reduced risk of malignant neoplasms and nonmelanoma skin cancers in transplant recipients. A meta-analysis by Yanik et al.²⁸⁴ revealed that sirolimus use in renal transplant recipients was associated with a lower risk of kidney cancer. This paradox arises from the fact that mTOR inhibitors are immunomodulators with a complex mechanism of action in adaptive immunity, capable of both promoting and suppressing immune responses.⁴⁰⁰ Therefore, the effect of mTOR inhibitors on CD8+ T cells may depend on the relative predominance of their immunostimulatory and immunosuppressive effects. Given the dual effects of mTOR inhibitors in suppressing posttransplantation rejection and reducing the risk of posttransplantation tumorigenesis, their potential application in preventing and treating specific types of posttransplantation tumors warrants further investigation. Furthermore, γδ T cells may offer a promising strategy for resolving this issue. Numerous studies have demonstrated that γδ T cells, which lack allogeneic heterozygosity, can be safely used in hematopoietic stem cell transplantation and can mediate natural antitumor responses.^{402, 403} Consequently, γδ T cells have potential applications for simultaneously preventing GvHD and posttransplantation tumors in specific types of transplantation. Numerous studies support this concept. For instance, in allo-HSCT recipients, γδ T cells are not believed to cause GvHD and may promote graft-versus-leukemia effects.⁴⁰⁴ Furthermore, Wu et al.^{405, 406} observed that the proportion of CD27+Vδ1 Tregs, a subpopulation of γδ Tregs, in grafts transplanted with peripheral blood stem cells was negatively correlated with acute GVHD. They also found that γδ Tregs exhibited a cytotoxic effect on tumor cells following granulocyte colony-stimulating factor treatment.^{405, 406} However, the specific mechanism of action and the potential role of γδ T cells in a broader range of transplantation settings require further investigation. Moreover, in addition to CAR-T therapy, TCR engineering, a relay cell therapy, has also shown potential for suppressing tumors after transplantation. Currently, T cells recognizing EBV antigens through natural TCRs have been successfully used to treat EBV-associated PTLD.⁴⁰⁷ Furthermore, modified TCR-genetically engineered virus-specific T cells targeting CMV and EBV were found to possess both antiviral activity and transgenic TCR-mediated tumor-targeting activity.⁴⁰⁸ Therefore, TCR engineering may also be a readily available cell therapy capable of specifically targeting tumors, and its further applications warrant additional investigation.