Immunosuppression refers to the deliberate or pathological reduction of the body's immune system activity, impairing its ability to detect and respond to pathogens such as bacteria, viruses, and fungi, as well as to identify and destroy abnormal or cancerous cells [1]. This condition can arise from a variety of causes, including medical treatments like chemotherapy and radiation therapy, underlying diseases such as HIV/AIDS and lymphoma, or be intentionally induced in clinical settings such as organ transplantation and the management of autoimmune diseases like rheumatoid arthritis and lupus [2]. The mechanisms of immunosuppression involve the suppression of key immune components, including T cells, B cells, and cytokine signaling pathways, leading to diminished immune responses through inhibition of cell activation, reduced antibody production, and induction of immune cell apoptosis [3]. While essential in preventing graft rejection and controlling autoimmune disorders, immunosuppressive therapy carries significant risks, including increased susceptibility to opportunistic infections such as cytomegalovirus and Pneumocystis jirovecii pneumonia, a higher incidence of malignancies like post-transplant lymphoproliferative disorder and non-melanoma skin cancers, and metabolic complications such as diabetes and hypertension [4]. Common immunosuppressive drugs include corticosteroids, calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors such as sirolimus, and biologic agents including basiliximab and rituximab, often used in combination to enhance efficacy while minimizing toxicity [5]. Emerging therapies aim to achieve more targeted immunosuppression with fewer systemic effects, such as engineered cellular immunotherapies and bispecific T cell engagers, reflecting ongoing efforts to improve precision and safety [6]. Effective management requires careful monitoring, including therapeutic drug monitoring and immune monitoring, as well as preventive measures like vaccination and infection control strategies to balance therapeutic benefits with potential complications.

Causes and Mechanisms of Immunosuppression

Immunosuppression arises from a diverse array of causes, including medical conditions, therapeutic interventions, and physiological processes, all of which impair the immune system's ability to mount effective responses against pathogens and malignant cells. The mechanisms underlying immunosuppression involve disruption of key immune components such as T cells, B cells, cytokine signaling, and immune regulatory pathways. These effects can be either deliberate, as in clinical settings like organ transplantation, or pathological, resulting from diseases such as HIV/AIDS or cancer.

Causes of Immunosuppression

Immunosuppression can be categorized into three primary etiological groups: disease-related, treatment-induced, and physiological.

Medical Conditions

Several diseases directly compromise immune function through various mechanisms. The most prominent example is HIV, which specifically targets and destroys CD4+ T cells, leading to progressive immune deficiency and the development of AIDS [7]. Hematologic malignancies such as leukemia and lymphoma disrupt normal hematopoiesis, crowding out healthy immune cells and impairing immune surveillance [8]. Autoimmune disorders like lupus and rheumatoid arthritis create a paradoxical state of immune dysregulation, where chronic inflammation and tissue damage can lead to overall immune dysfunction [8].

Congenital immunodeficiency disorders, such as Severe Combined Immunodeficiency (SCID) and Common Variable Immunodeficiency (CVID), result from genetic defects in immune system development and are typically diagnosed in childhood [10]. Other chronic conditions, including diabetes, chronic kidney disease, liver cirrhosis, and malnutrition, are associated with weakened immune responses due to metabolic disturbances and impaired production of immune components [11]. The natural aging process, known as immunosenescence, also contributes to immunosuppression by gradually diminishing both innate and adaptive immunity, increasing infection risk in older adults [12].

Medical Treatments

Therapeutic interventions are a common cause of iatrogenic immunosuppression. In the context of organ transplantation, immunosuppressive drugs are deliberately administered to prevent graft rejection by suppressing the recipient's immune response to the foreign tissue [13]. Similarly, in autoimmune diseases, immunosuppressants are used to control the overactive immune system that attacks the body's own tissues [14].

Cancer therapies, particularly chemotherapy and radiation therapy, are major contributors to immunosuppression. These treatments target rapidly dividing cells, including immune cells like lymphocytes, leading to reduced white blood cell counts and impaired immune surveillance [15]. Corticosteroids, such as prednisone, are widely used for their potent anti-inflammatory effects and broadly suppress immune function by inhibiting T cell activation and cytokine production [15].

Other Causes

Non-disease and non-treatment factors also contribute to immunosuppression. , especially deficiencies in protein, vitamins (e.g., vitamin A, C, D), and minerals like zinc, can severely impair immune cell function and antibody production [12]. Chronic infections can exhaust immune resources, leading to a state of immune dysfunction. Medical procedures such as bone marrow and stem cell transplants involve conditioning regimens that cause temporary or prolonged immunosuppression to allow engraftment of donor cells [1].

Mechanisms of Immunosuppression

The mechanisms by which immunosuppression occurs are multifaceted, targeting various stages of the immune response. These mechanisms can be broadly classified into the suppression of immune cell function and the modulation of immune regulatory pathways.

Suppression of Immune Cell Function

The core mechanisms of immunosuppression involve the direct inhibition of key immune cells and their functions. Immunosuppressive agents can inhibit the activation and proliferation of T cells and B cells, which are central to adaptive immunity [3]. This leads to a reduction in the production of antibodies by B cells and a diminished capacity for cell-mediated immune responses. The suppression of cytokine release, particularly critical signaling molecules like interleukin-2 (IL-2), disrupts the communication between immune cells necessary for a coordinated defense. Some drugs induce the programmed cell death, or apoptosis, of immune cells, further depleting the immune system's arsenal [3].

Modulation of Immune Regulatory Pathways

The body's natural mechanisms for maintaining immune tolerance also play a role in immunosuppression. Physiological immunosuppression, or immune tolerance, prevents the immune system from attacking self-tissues and is maintained through processes like central and peripheral tolerance. Central tolerance occurs in the thymus and bone marrow, where autoreactive T and B cells are eliminated during development [21]. Peripheral tolerance acts as a secondary safeguard and involves mechanisms such as anergy (functional inactivation of T cells), activation-induced cell death, and the action of regulatory T cells (Tregs) [22].

Tregs are a specialized subset of CD4+ T cells that actively suppress immune activity to maintain homeostasis. They exert their effects through multiple mechanisms, including the secretion of inhibitory cytokines like IL-10 and TGF-β, cell-contact-dependent suppression via molecules like CTLA-4 and LAG-3, and metabolic disruption by consuming IL-2 or producing adenosine [23]. The immune checkpoint pathways, such as CTLA-4 and PD-1, function as physiological brakes on T cell activation, preventing excessive immune responses and autoimmunity [24]. In therapeutic settings, these natural regulatory mechanisms are often mimicked or enhanced by immunosuppressive drugs to achieve clinical goals.

Clinical Applications in Transplantation and Autoimmune Diseases

Immunosuppression is a cornerstone of modern medicine, with critical applications in two major clinical domains: organ transplantation and the management of autoimmune diseases. In both contexts, the goal is to modulate the immune system to prevent harmful responses—either against a transplanted organ or against the body’s own tissues—while carefully balancing the increased risks of infection and malignancy. These applications require tailored, often lifelong, therapeutic strategies that integrate pharmacologic, monitoring, and preventive measures to optimize patient outcomes.

Organ Transplantation: Preventing Allograft Rejection

In solid organ transplantation—such as kidney, liver, heart, and lung—the recipient’s immune system recognizes the transplanted tissue as foreign due to differences in human leukocyte antigens (HLAs), triggering alloreactive T and B cell responses that can lead to graft rejection. To prevent this, patients receive lifelong immunosuppressive regimens that are typically initiated with a three-phase approach: induction, maintenance, and rejection therapy.

Induction therapy involves the administration of potent biologic agents immediately before, during, or after transplantation to rapidly suppress the immune system and reduce the risk of early rejection. This phase commonly uses monoclonal antibodies such as basiliximab, which targets the CD25 subunit of the interleukin-2 receptor (IL-2R) on activated T cells, thereby inhibiting their proliferation. Alternatively, lymphocyte-depleting agents like anti-thymocyte globulin (ATG) or alemtuzumab may be used, particularly in high-immunologic-risk patients, such as those with high panel-reactive antibodies (PRA) or prior transplants [25].

Maintenance therapy follows induction and is designed to sustain long-term graft survival. It typically consists of a combination of drugs targeting different immune pathways to enhance efficacy while minimizing toxicity. The backbone of most regimens includes a calcineurin inhibitor such as tacrolimus or cyclosporine, which blocks T cell activation by inhibiting calcineurin and preventing nuclear translocation of NFAT, thereby suppressing interleukin-2 (IL-2) production [26]. This is combined with an antiproliferative agent like mycophenolate mofetil (MMF) or azathioprine, which inhibits purine synthesis and lymphocyte proliferation, and often corticosteroids such as prednisone for their broad anti-inflammatory effects [25]. In select cases, mTOR inhibitors such as sirolimus or everolimus may replace calcineurin inhibitors to reduce nephrotoxicity or malignancy risk [26].

Rejection therapy is employed when acute rejection occurs, typically involving high-dose corticosteroids or antibody-based therapies like ATG to rapidly suppress the immune response [29]. Long-term success depends on strict adherence to medication, as nonadherence is a major risk factor for graft rejection and failure [25].

Autoimmune Diseases: Controlling Pathological Immune Responses

In autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and lupus nephritis, the immune system mistakenly attacks the body’s own tissues, leading to chronic inflammation and organ damage. Immunosuppressive therapy aims to control this aberrant immune activity, often using a tiered approach based on disease severity and organ involvement.

For SLE, foundational therapy includes hydroxychloroquine, which reduces flares and improves survival, combined with glucocorticoids such as prednisone to control disease activity. In severe cases involving the kidneys or central nervous system, high-dose intravenous methylprednisolone pulses may be used. For moderate to severe disease, particularly lupus nephritis, induction therapy typically involves mycophenolate mofetil (MMF) or low-dose intravenous cyclophosphamide (CYC), followed by maintenance therapy with MMF or azathioprine [31]. Biologic agents such as belimumab, which targets B-cell activating factor (BAFF), and rituximab, an anti-CD20 B-cell depleting agent, are used in refractory cases [32].

In RA, the first-line treatment is methotrexate, a conventional synthetic disease-modifying antirheumatic drug (csDMARD), often combined with low-dose prednisone as bridging therapy. For patients with high disease activity or poor prognostic factors, early escalation to biologic DMARDs (bDMARDs) such as tumor necrosis factor (TNF) inhibitors (e.g., adalimumab, infliximab) or interleukin-6 (IL-6) receptor antagonists (e.g., tocilizumab) is recommended. Targeted synthetic DMARDs (tsDMARDs) like JAK inhibitors (e.g., tofacitinib, upadacitinib) offer oral alternatives with rapid onset of action [33].

For IBD, including Crohn’s disease and ulcerative colitis, biologics such as anti-TNF agents, vedolizumab, and risankizumab are highly effective in inducing and maintaining remission, particularly in biologically naïve patients [34]. In contrast, methotrexate monotherapy shows limited efficacy, particularly for induction of remission [35]. JAK inhibitors have also demonstrated promising results in recent studies [36].

Individualized Treatment and Risk Stratification

The selection of immunosuppressive regimens in both transplantation and autoimmune diseases is highly individualized, driven by patient-specific risk factors. In transplantation, immunologic risk—determined by HLA mismatching, donor-specific antibodies (DSAs), and sensitization (high PRA)—guides the intensity of induction and maintenance therapy [37]. Infection and malignancy risk also influence therapy; for example, older patients or those with prior cancer may benefit from regimens incorporating mTOR inhibitors due to their antiproliferative properties [38]. Pharmacogenetic factors, such as CYP3A5 polymorphisms, affect tacrolimus metabolism and dosing requirements, necessitating genotype-guided strategies [39].

In autoimmune diseases, treatment escalation is guided by disease activity and response. The treat-to-target strategy mandates regular monitoring and therapy adjustment until remission or low disease activity is achieved [40]. For refractory cases, advanced therapies such as hematopoietic stem cell transplantation (HSCT) or CAR T-cell therapy are under investigation [41].

Emerging Strategies for Precision Immunosuppression

Advancements in immune monitoring and HLA typing are transforming the field by enabling more precise risk assessment and therapy personalization. High-resolution HLA typing using next-generation sequencing (NGS) allows for allele-level matching and epitope-based mismatch analysis, which correlates more strongly with rejection risk than traditional antigen matching [42]. Non-invasive biomarkers such as donor-derived cell-free DNA (dd-cfDNA) in recipient plasma are used to detect graft injury and rejection earlier than traditional methods [43]. Gene expression profiling and urinary chemokines like CXCL9 and CXCL10 provide real-time insights into allograft health and immune activation [44].

Pharmacogenomics plays a growing role, with CYP3A5 and ABCB1 variants guiding tacrolimus dosing to achieve target concentrations more rapidly and safely [45]. Functional immune assays such as the Immunobiogram (IMBG) assess individual lymphocyte responsiveness to immunosuppressants ex vivo, helping to identify under- or over-immunosuppressed patients [46].

Balancing Efficacy and Safety

The long-term success of immunosuppressive therapy depends on balancing graft or disease control with the risks of infection and malignancy. Strategies include CNI minimization or withdrawal in low-risk patients, conversion to mTOR inhibitors in those with high cancer risk, and steroid-sparing regimens to reduce metabolic complications [47]. Infection prophylaxis with agents like trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia and antiviral prophylaxis for CMV is standard in high-risk patients [48]. Vaccination before immunosuppression and regular cancer screening are essential components of long-term management [49].

In summary, immunosuppression in transplantation and autoimmune diseases is a complex, dynamic process that requires individualized, evidence-based approaches. By integrating pharmacologic strategies, immune monitoring, and preventive care, clinicians can optimize therapeutic outcomes while minimizing complications, paving the way for safer and more effective long-term management.

Major Classes of Immunosuppressive Drugs and Their Mechanisms

Immunosuppressive drugs are pharmacological agents designed to modulate or suppress the immune system's activity, primarily used to prevent organ transplant rejection and manage autoimmune diseases. These drugs target different stages of immune cell activation and proliferation, enabling tailored therapeutic strategies that balance efficacy with safety. The major classes include calcineurin inhibitors, mTOR inhibitors, anti-proliferative agents, corticosteroids, and biologic agents, each with distinct molecular targets and mechanisms of action.

Calcineurin Inhibitors: Suppressing T Cell Activation

Calcineurin inhibitors, such as cyclosporine A and tacrolimus (FK506), are cornerstone therapies in transplantation and autoimmune disease management due to their potent suppression of T cell activation. Upon engagement of the T cell receptor (TCR) by antigen-presenting cells, intracellular calcium levels rise, activating the calcium/calmodulin-dependent phosphatase calcineurin [50]. Activated calcineurin dephosphorylates the nuclear factor of activated T cells (NFAT), allowing it to translocate into the nucleus and initiate transcription of key cytokines, particularly interleukin-2 (IL-2), which drives T cell proliferation and effector function [51].

These drugs inhibit this pathway by forming complexes with intracellular immunophilins: cyclosporine binds to cyclophilin, while tacrolimus binds to FK-binding protein 12 (FKBP12) [52]. The resulting drug-immunophilin complexes then bind to and inhibit calcineurin, thereby blocking NFAT dephosphorylation and nuclear translocation. This suppresses IL-2 gene expression and halts the autocrine signaling loop required for T cell clonal expansion [53]. As a result, calcineurin inhibitors effectively block the initiation of adaptive immune responses, making them essential in preventing acute rejection after solid organ transplantation [54].

Despite their shared mechanism, tacrolimus is approximately 10–100 times more potent than cyclosporine on a molar basis in inhibiting IL-2 production and T cell activation [55]. Pharmacokinetic differences also influence clinical use: tacrolimus has more consistent oral bioavailability (20–25%) compared to cyclosporine (25–50%), and its shorter half-life (12–15 hours) necessitates twice-daily dosing, although extended-release formulations allow once-daily administration [56]. Therapeutic drug monitoring (TDM) is critical for both agents due to narrow therapeutic indices and significant inter-patient variability influenced by genetic polymorphisms in CYP3A4 and CYP3A5 enzymes [57].

mTOR Inhibitors: Modulating Immune Cell Proliferation and Differentiation

mTOR inhibitors, including sirolimus (rapamycin) and everolimus, target the mammalian target of rapamycin (mTOR), a serine/threonine kinase that integrates signals from growth factors, nutrients, and energy status to regulate cell growth, metabolism, and proliferation [58]. Unlike calcineurin inhibitors, mTOR inhibitors do not interfere with early T cell activation or IL-2 production. Instead, they block the cellular response to IL-2 by inhibiting mTOR complex 1 (mTORC1), which is essential for protein synthesis, metabolic reprogramming (e.g., glycolysis), and progression through the G1 phase of the cell cycle [59].

Sirolimus binds to FKBP12, and this complex inhibits mTORC1, suppressing ribosomal biogenesis and cap-dependent mRNA translation required for T cell proliferation [60]. This mechanism allows mTOR inhibitors to act downstream of calcineurin, providing a complementary approach when used in combination regimens. Notably, mTOR inhibition differentially affects T cell subsets: it suppresses effector T cells (Teff) while promoting the expansion and functional stability of regulatory T cells (Tregs), which are critical for maintaining immune tolerance [61]. This unique immunomodulatory profile contributes to reduced alloreactivity and may lower the risk of chronic rejection and post-transplant malignancies [62].

Clinically, mTOR inhibitors are often used as alternatives to calcineurin inhibitors in patients at high risk for nephrotoxicity or cancer, given their potential chemopreventive properties [63]. However, they are associated with side effects such as hyperlipidemia, impaired wound healing, and pneumonitis, requiring careful patient selection and monitoring [64].

Anti-Proliferative Agents: Inhibiting Nucleotide Synthesis

Anti-proliferative agents, such as mycophenolate mofetil (MMF) and azathioprine, primarily inhibit DNA synthesis, thereby preventing lymphocyte proliferation during clonal expansion in response to antigenic stimulation. These agents are commonly used in combination with calcineurin or mTOR inhibitors to enhance immunosuppressive efficacy [65].

Mycophenolate mofetil is hydrolyzed to mycophenolic acid (MPA), which selectively and reversibly inhibits inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo pathway of guanine nucleotide synthesis [66]. Lymphocytes are highly dependent on this pathway for purine synthesis, unlike other cells that can utilize salvage pathways. Depletion of guanosine nucleotides leads to arrest in the S phase of the cell cycle, impairing DNA replication and T and B cell proliferation [67]. MMF is widely used in transplantation due to its potent antiproliferative effects and relatively favorable safety profile, though it carries risks of gastrointestinal toxicity and bone marrow suppression [4].

Azathioprine, a prodrug metabolized to 6-mercaptopurine, is further converted into thioguanine nucleotides that incorporate into DNA and RNA, causing mismatch errors and inhibition of purine synthesis [65]. This disrupts nucleic acid metabolism and induces cell cycle arrest, particularly in rapidly dividing immune cells. While effective, azathioprine is associated with hepatotoxicity and photosensitization, which increases the risk of nonmelanoma skin cancers [70].

Corticosteroids: Broad Anti-Inflammatory and Immunosuppressive Effects

Corticosteroids, such as prednisone and methylprednisolone, exert broad immunosuppressive and anti-inflammatory effects by modulating multiple aspects of immune function. They bind to glucocorticoid receptors in the cytoplasm, which translocate to the nucleus and either transactivate anti-inflammatory genes or transrepress pro-inflammatory transcription factors such as NF-κB and AP-1 [71]. This results in reduced expression of cytokines (e.g., IL-1, IL-6, TNF-α), chemokines, and adhesion molecules, thereby dampening both innate and adaptive immune responses.

Corticosteroids also inhibit leukocyte migration, reduce antigen presentation by dendritic cells and macrophages, and promote apoptosis of lymphocytes [72]. Their rapid onset of action makes them valuable for managing acute flares in autoimmune diseases and as part of induction therapy in transplantation. However, long-term use is associated with significant adverse effects, including steroid-induced diabetes, osteoporosis, avascular necrosis, cataracts, and increased susceptibility to infections [73]. Consequently, corticosteroid-sparing or steroid-free regimens are increasingly adopted to minimize metabolic complications while maintaining disease control [74].

Biologic Agents: Targeted Immunomodulation

Biologic immunosuppressants are monoclonal antibodies or fusion proteins that target specific immune components, offering more selective immunomodulation compared to broad-spectrum agents. Key examples include basiliximab, rituximab, and belatacept.

Basiliximab is an interleukin-2 receptor antagonist (IL-2RA) that binds to the alpha subunit (CD25) of the IL-2 receptor on activated T cells, preventing IL-2 from initiating clonal expansion [75]. It is used as induction therapy in kidney transplantation, administered shortly after graft reperfusion, and is associated with a favorable safety profile due to its non-depleting mechanism [76].

Rituximab targets the CD20 antigen on B cells, leading to their depletion through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct induction of apoptosis [77]. It is used in desensitization protocols for highly sensitized transplant candidates and in the treatment of B cell–mediated autoimmune diseases such as systemic lupus erythematosus and ANCA-associated vasculitis [78]. However, rituximab increases the risk of hypogammaglobulinemia and serious infections, including reactivation of hepatitis B virus and progressive multifocal leukoencephalopathy (PML) [79].

Belatacept, a fusion protein that blocks CD28-mediated costimulation by binding to CD80/CD86 on antigen-presenting cells, offers a calcineurin inhibitor–free alternative in transplantation. By inhibiting the second signal required for full T cell activation, belatacept reduces the risk of nephrotoxicity and metabolic complications associated with calcineurin inhibitors, making it particularly beneficial for preserving long-term renal function [47].

The integration of these diverse drug classes into combination regimens allows for synergistic immunosuppression with reduced toxicity. For example, triple therapy in transplantation typically includes a calcineurin inhibitor, an antimetabolite, and corticosteroids, with adjustments based on patient risk factors, organ type, and institutional protocols [25]. Emerging strategies focus on achieving antigen-specific tolerance through engineered cellular therapies such as chimeric antigen receptor regulatory T cells (CAR-Tregs), which aim to suppress pathological immune responses without compromising systemic immunity [82].

Risks and Complications of Long-Term Immunosuppression

Long-term immunosuppression, while essential for preventing graft rejection in transplant recipients and controlling autoimmune diseases, significantly increases the risk of various complications. The suppression of immune function impairs the body’s ability to detect and eliminate pathogens and malignant cells, leading to heightened susceptibility to infections, malignancies, and other systemic complications. These risks are influenced by the type, intensity, and duration of immunosuppressive therapy, as well as patient-specific factors such as age, comorbidities, and genetic predispositions [4].

Increased Susceptibility to Infections

One of the most significant risks of long-term immunosuppression is the heightened vulnerability to infections, including both common and opportunistic pathogens. The immune system's diminished capacity to mount effective responses allows bacteria, viruses, fungi, and parasites to cause severe disease. Patients are particularly susceptible to opportunistic infections—those that typically do not affect immunocompetent individuals—due to impaired cellular and humoral immunity [84].

Common infections in immunosuppressed individuals include bacterial infections caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, particularly when humoral immunity is compromised [84]. Viral reactivations such as cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV) are frequent, especially in transplant recipients [86]. Fungal infections like those caused by Candida and Aspergillus species are common in patients with neutropenia or impaired cellular immunity [86]. Parasitic infections, including Pneumocystis jirovecii pneumonia, also occur depending on the degree of immunosuppression [84].

The risk of severe outcomes from respiratory viruses, including SARS-CoV-2, is disproportionately high in immunocompromised individuals. Real-world evidence confirms that despite vaccination, this population remains at increased risk for severe COVID-19 [89]. Prophylactic strategies, including antimicrobial prophylaxis and vaccination, are critical components of infection prevention [90].

Higher Risk of Malignancies

Long-term immunosuppression is strongly associated with an increased incidence of malignancies, primarily due to impaired immune surveillance—the body’s natural ability to identify and destroy cancerous or precancerous cells. Organ transplant recipients, in particular, face a significantly elevated cancer risk, with studies indicating that up to 40% may develop cancer during their lifetime [91]. The risk correlates with the duration and intensity of immunosuppressive therapy, with higher cumulative exposure leading to greater oncogenic potential [92].

Common malignancies in immunosuppressed patients include post-transplant lymphoproliferative disorder (PTLD), often driven by Epstein-Barr virus (EBV) reactivation, and various solid tumors such as skin cancers (especially squamous cell carcinoma), lung, liver, and kidney cancers [7]. Many of these cancers are linked to oncogenic viruses whose replication is normally controlled by an intact immune system. In immunosuppressed individuals, unchecked viral activity promotes carcinogenesis. Key virus-associated cancers include Kaposi sarcoma (linked to human herpesvirus 8), cervical and oropharyngeal cancers (associated with human papillomavirus), and hepatocellular carcinoma (associated with hepatitis B and C viruses) [7].

Specific immunosuppressive agents contribute differentially to cancer risk. Calcineurin inhibitors like cyclosporine and tacrolimus are associated with increased risks of skin cancers and hepatocellular carcinoma, while purine synthesis inhibitors like azathioprine are linked to nonmelanoma skin cancers due to photosensitization and DNA damage [70]. In contrast, mTOR inhibitors such as sirolimus and everolimus may have antitumor properties and are sometimes used to mitigate cancer risk in transplant recipients [64].

Organ Toxicity and Chronic Diseases

Many immunosuppressive drugs have direct toxic effects on vital organs, particularly the kidneys and liver. Calcineurin inhibitors are well-known for their nephrotoxic effects, causing afferent arteriolar vasoconstriction and chronic interstitial fibrosis, which can lead to progressive kidney dysfunction. Up to 20% of liver transplant recipients develop chronic kidney disease within five years of transplantation, largely due to calcineurin inhibitor use [63]. Regular monitoring of renal function and therapeutic drug levels is essential to minimize this risk [98].

Liver dysfunction can also occur with certain immunosuppressants, including methotrexate and azathioprine, necessitating routine monitoring of liver enzymes [99]. Additionally, some agents contribute to metabolic disturbances that increase the risk of cardiovascular disease. Corticosteroids and tacrolimus are associated with new-onset diabetes mellitus, while calcineurin inhibitors frequently cause hypertension [100]. Dyslipidemia, characterized by abnormal cholesterol and triglyceride levels, further elevates the long-term risk of atherosclerosis, heart attacks, and strokes [100].

Metabolic and Cardiovascular Complications

Immunosuppressive therapy often leads to a constellation of metabolic complications that collectively increase cardiovascular risk. Corticosteroids are particularly implicated in inducing insulin resistance, hyperglycemia, and steroid-induced diabetes, with up to 19% of long-term users developing the condition [73]. They also contribute to central obesity, hepatic steatosis, and dyslipidemia, all of which are components of metabolic syndrome [103].

Hypertension is another common adverse effect, especially with calcineurin inhibitors, and contributes to the high rates of cardiovascular disease observed in transplant recipients [104]. The combination of diabetes, hypertension, and dyslipidemia creates a pro-atherogenic environment, making cardiovascular disease a leading cause of mortality in this population. Management strategies include aggressive control of modifiable risk factors, lifestyle interventions, and steroid-sparing regimens when possible [105].

Other Side Effects and Complications

Additional complications vary by specific drug but may include gastrointestinal issues such as nausea, vomiting, and diarrhea, particularly with mycophenolate mofetil [106]. Neurological effects like tremors and headaches are commonly associated with tacrolimus, while cyclosporine can cause gum overgrowth [99]. Bone marrow suppression, leading to anemia, leukopenia, or thrombocytopenia, is a risk with drugs like azathioprine and mycophenolate [108].

Chronic use of corticosteroids is also linked to osteoporosis, avascular necrosis, cataracts, and adrenal suppression, necessitating preventive measures such as calcium and vitamin D supplementation and bisphosphonate therapy [109]. These long-term complications underscore the importance of individualized therapy, regular monitoring, and proactive management to optimize patient outcomes while minimizing toxicity [104].

Monitoring and Management of Immunosuppressive Therapy

The monitoring and management of immunosuppressive therapy is a critical, multidimensional process aimed at maintaining therapeutic efficacy while minimizing adverse effects such as infections, malignancies, and organ toxicity. This balance is achieved through a combination of therapeutic drug monitoring (TDM), immune function assessment, infection prophylaxis, and individualized treatment strategies guided by patient-specific risk factors and evolving biomarker data [111][112]. The complexity of this task is heightened by significant inter- and intra-patient variability in pharmacokinetics, which is particularly pronounced with agents like calcineurin inhibitors (CNIs) such as tacrolimus and cyclosporine, which have narrow therapeutic indices and are susceptible to numerous drug interactions [113][114].

Therapeutic Drug Monitoring and Pharmacokinetic Management

Therapeutic drug monitoring (TDM) is a cornerstone of immunosuppressive therapy, enabling clinicians to individualize dosing based on measured drug concentrations in blood or plasma. The primary goal is to maintain drug levels within a narrow therapeutic window to prevent graft rejection or autoimmune flares while avoiding toxicity [115][116]. For CNIs, the most common method is trough concentration monitoring (C0), where blood is drawn immediately before the next dose. Target trough levels for tacrolimus vary by organ type and time post-transplant; for example, in kidney transplantation, initial targets range from 5–10 ng/mL, gradually tapering to 3–7 ng/mL over time [115]. For cyclosporine, the microemulsion formulation (Neoral) has led to the adoption of C2 monitoring (2 hours post-dose), which correlates better with total drug exposure (AUC) and clinical outcomes than trough levels [118].

For agents with high pharmacokinetic variability, such as mycophenolate mofetil (MMF), area under the curve (AUC) monitoring is more predictive of efficacy and toxicity than trough levels alone. However, due to practical constraints, limited sampling strategies (LSS) using 3–4 time points post-dose are often employed to estimate AUC with acceptable accuracy [119][120]. TDM is most intensive during the early post-transplant period and whenever changes in medication, gastrointestinal function, or organ function occur, with guidelines from organizations like KDIGO and the International Society for Heart and Lung Transplantation (ISHLT) recommending frequent monitoring until stable levels are achieved [116][26].

Management of Drug Interactions and Pharmacogenomics

The metabolism of key immunosuppressants, particularly tacrolimus and cyclosporine, is primarily mediated by the cytochrome P450 (CYP450) enzyme system, specifically CYP3A4 and CYP3A5, making them highly susceptible to drug interactions [123][124]. Inhibitors of CYP3A4, such as azole antifungals (e.g., ketoconazole, voriconazole), macrolide antibiotics (e.g., clarithromycin), and protease inhibitors (e.g., ritonavir), can significantly increase blood concentrations of CNIs, raising the risk of nephrotoxicity and neurotoxicity. For example, co-administration with ketoconazole may require a 50–80% dose reduction of tacrolimus, with TDM guiding adjustments [125][126]. Conversely, CYP3A4 inducers like phenytoin, carbamazepine, and rifampin can accelerate CNI metabolism, leading to subtherapeutic levels and increased rejection risk [127].

Dietary factors also modulate CYP3A4 activity; grapefruit juice inhibits intestinal CYP3A4 and P-glycoprotein (P-gp), increasing tacrolimus bioavailability and peak concentrations [128][129]. Genetic polymorphisms in CYP3A5 significantly influence tacrolimus pharmacokinetics, with CYP3A5 expressers (*1/*1 or *1/*3) requiring higher doses than non-expressers (*3/*3) to achieve target trough levels [123][131]. Pharmacogenetic testing is increasingly used to guide initial dosing, particularly in kidney transplantation, to achieve therapeutic levels more rapidly and reduce early rejection risk [132].

Risk Mitigation for Infection and Malignancy

Long-term immunosuppression increases susceptibility to infections and malignancies, necessitating proactive risk mitigation strategies. For infection prevention, antimicrobial prophylaxis is recommended based on risk stratification. For example, trimethoprim-sulfamethoxazole is standard for preventing Pneumocystis jirovecii pneumonia in high-risk transplant recipients, while antiviral prophylaxis (e.g., valganciclovir) is used to prevent cytomegalovirus (CMV) in seropositive patients [133][134]. Patients should be screened for latent infections (e.g., tuberculosis, hepatitis B/C) before initiating therapy [135].

For malignancy prevention, structured surveillance is vital. In transplant recipients, regular cancer screening is recommended, including enhanced screening for non-melanoma skin cancer, cervical cancer (via Pap smears and HPV testing), and other site-specific cancers based on individual risk factors [136]. Strategies to reduce malignancy risk include switching from calcineurin inhibitors to mTOR inhibitors (e.g., sirolimus, everolimus), which have antiproliferative properties and are associated with lower rates of virus-associated cancers like post-transplant lymphoproliferative disorder (PTLD) and Kaposi sarcoma [137]. Rigorous sun protection and dermatologic care are essential due to the high incidence of UV-induced skin cancers [138].

Individualized Therapy and Emerging Biomarkers

The selection of immunosuppressive regimens is highly individualized, driven by patient-specific risk factors such as immunologic risk (e.g., HLA mismatch, donor-specific antibodies), infection and malignancy history, pharmacogenetics, and psychosocial factors [139]. For instance, patients with a history of cancer may benefit from regimens incorporating mTOR inhibitors, while those with marginal renal function may be candidates for conversion to belatacept, a costimulation blocker associated with superior renal function [47]. Emerging tools in immune monitoring, such as donor-derived cell-free DNA (dd-cfDNA), gene expression profiling, and the Immunobiogram (IMBG) test, are enhancing the ability to personalize immunosuppression by providing real-time insights into allograft health and the net state of immunosuppression [141][142]. These advancements support a shift toward dynamic, response-adapted regimens that optimize long-term outcomes.

Prophylactic and Preventive Strategies for Infections

Individuals with immunosuppression face a significantly increased risk of infections due to impaired immune defenses, whether from underlying conditions like HIV/AIDS or therapies such as chemotherapy, organ transplantation, or treatment for autoimmune diseases. Effective prophylactic and preventive strategies are essential to reduce the incidence and severity of both common and opportunistic infections. These strategies include targeted antimicrobial prophylaxis, vaccination, lifestyle modifications, and vigilant monitoring based on the type and intensity of immunosuppression.

Antimicrobial Prophylaxis for Key Opportunistic Infections

Prophylactic antimicrobial therapy is a cornerstone of infection prevention in high-risk immunocompromised patients, particularly in the early post-transplant period or during intense immunosuppressive regimens.

Cytomegalovirus (CMV) Prophylaxis

CMV is a major cause of morbidity and mortality in immunocompromised individuals, especially solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients. Prophylaxis is risk-stratified based on donor (D) and recipient (R) serostatus, with D+/R− patients at highest risk for primary infection and disease. Standard prophylactic agents include valganciclovir or intravenous ganciclovir, administered for 3–6 months post-transplant, with extended durations (up to 12 months) recommended for high-risk lung or small bowel transplant recipients [143]. In HCT recipients, letermovir is approved for CMV prophylaxis in CMV-seropositive patients from day 0 to day 100 post-transplant, with potential extension to day 200 in high-risk cases [144]. Letermovir offers superior efficacy without the myelosuppressive effects of ganciclovir, making it a preferred option in this population [145].

Pneumocystis jirovecii Pneumonia (PCP) Prophylaxis

PCP prophylaxis is critical in patients with profound T-cell immunodeficiency. Trimethoprim-sulfamethoxazole (TMP-SMX) is the gold standard due to its high efficacy, low cost, and additional activity against Toxoplasma gondii and some bacterial pathogens [146]. It is typically administered as one double-strength tablet daily or three times weekly [147]. For patients intolerant to TMP-SMX, alternatives include dapsone, atovaquone, or aerosolized pentamidine [148]. In HIV-infected patients, prophylaxis is indicated when CD4 counts fall below 200 cells/mm³ and should continue until immune reconstitution on antiretroviral therapy (ART) [149]. In transplant and oncology patients, prophylaxis is recommended for those receiving high-dose corticosteroids (≥20 mg prednisone daily for ≥1 month) or T-cell depleting agents like alemtuzumab, and should extend for the duration of high-risk immunosuppression [150].

Invasive Fungal Infection (IFI) Prophylaxis

Antifungal prophylaxis is essential for patients with prolonged neutropenia, graft-versus-host disease (GVHD), or high-dose corticosteroid use. High-risk populations include allogeneic hematopoietic stem cell transplant (HSCT) recipients and patients with acute myeloid leukemia (AML) undergoing induction chemotherapy. Mold-active antifungals such as posaconazole and voriconazole are recommended for prophylaxis in these groups [151]. Posaconazole has demonstrated superior efficacy in preventing invasive aspergillosis compared to fluconazole [152]. Fluconazole is effective against Candida species but does not protect against molds and is reserved for lower-risk patients [153]. Prophylaxis duration is individualized, typically continuing until engraftment and resolution of neutropenia in HSCT recipients, and for 3–6 months post-transplant in high-risk SOT recipients such as lung transplant patients [154].

Vaccination Strategies for Immunocompromised Individuals

Vaccination is a critical component of infection prevention, though immunogenicity may be suboptimal in immunocompromised hosts. Strategies must be tailored to the underlying cause and degree of immune suppression.

Recommended Inactivated Vaccines

Non-live vaccines are generally safe and strongly recommended. The CDC advises administering inactivated vaccines at least two weeks before initiating immunosuppressive therapy when possible [155]. Key vaccines include:

  • Influenza (inactivated): Annual vaccination is recommended, with high-dose or adjuvanted formulations preferred for solid organ transplant recipients to enhance immunogenicity [156].
  • Pneumococcal vaccines: Sequential administration of PCV20 or PCV15 followed by PPSV23 is recommended to protect against invasive pneumococcal disease [157].
  • Hepatitis B: Vaccination is recommended, with post-vaccination serological testing to confirm response due to potentially blunted immunity [155].
  • Tetanus, diphtheria, pertussis (Tdap) and Haemophilus influenzae type b (Hib) are also recommended.
  • mRNA-based COVID-19 vaccines: Updated formulations are recommended for all immunocompromised individuals aged ≥6 months, with additional doses to improve seroconversion rates, which can be as low as ~34% after two doses in transplant recipients [159].
  • RSV vaccines (e.g., Arexvy, Abrysvo): Recommended for immunocompromised adults and adolescents [160].

Guidance on Live Vaccines

Live attenuated vaccines—including measles, mumps, and rubella (MMR), varicella, and live-attenuated influenza vaccine (LAIV)—are generally contraindicated in severely immunocompromised individuals due to the risk of disseminated infection [161]. Exceptions include HIV-infected individuals with CD4+ T cell counts ≥200 cells/µL, who may safely receive MMR and varicella vaccines [162]. The recombinant zoster vaccine (RZV) is preferred over the live zoster vaccine (ZVL) and is recommended for immunocompromised adults aged ≥19 years, regardless of CD4 count [163].

Lifestyle and Hygiene Measures

Non-pharmacologic strategies are vital for reducing infection risk. Frequent handwashing with soap and water for at least 20 seconds, especially before eating and after using the bathroom, is one of the most effective preventive measures [164]. Alcohol-based hand sanitizers with at least 60% alcohol are recommended when soap and water are unavailable [165]. Patients should avoid close contact with individuals who are sick or have recently received live vaccines, limit exposure to crowded indoor settings during peak respiratory virus seasons, and wear masks in high-risk environments [166].

Food safety is another critical area. Immunocompromised individuals should avoid unpasteurized dairy products, juices, and raw or undercooked eggs, meat, seafood, and sprouts [167]. Foods should be cooked to safe internal temperatures (e.g., poultry to 165°F), fruits and vegetables washed thoroughly, and cross-contamination prevented by using separate cutting boards and utensils for raw and cooked foods. Good oral hygiene and skin care help prevent infections from cuts or sores, and electric razors are recommended to minimize skin nicks [168]. Patients should also avoid gardening or handling soil and animal waste, which may contain harmful fungi or bacteria.

Monitoring and Risk Stratification

Effective infection prevention requires individualized risk assessment and ongoing monitoring. The "net state of immunosuppression"—a composite of drug type, dose, duration, comorbidities, and environmental exposures—determines individual infection risk [72]. Regular monitoring for viral reactivations, such as CMV DNAemia and EBV DNAemia, allows for preemptive reduction of immunosuppression to prevent end-organ disease [170]. Biomarkers like Torque Teno Virus (TTV) are being explored as indicators of overall immunosuppressive burden [171]. Clinicians should also screen for latent infections (e.g., tuberculosis, hepatitis B) before initiating therapy and consider antimicrobial prophylaxis based on patient-specific risk factors such as lymphopenia (CD4+ <250/µL) or neutropenia (neutrophils <500/mm³) [172]. Vaccination of household members and close contacts creates a "cocoon" of protection, particularly for respiratory pathogens like influenza, RSV, and SARS-CoV-2 [173].

Vaccination Guidelines for Immunocompromised Individuals

Vaccination is a critical component of preventive care for immunocompromised individuals, who face heightened risks of severe and life-threatening infections due to impaired immune function. The primary goal of vaccination in this population is to provide protection against vaccine-preventable diseases while minimizing the risk of adverse events, particularly from live vaccines. Current guidelines from organizations such as the Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America (IDSA) emphasize individualized, evidence-based strategies that consider the underlying cause and degree of immunosuppression, the type of immunosuppressive therapy, and the patient’s vaccination history [155].

General Principles and Timing of Vaccination

Optimal vaccination outcomes depend on the timing of vaccine administration relative to the initiation or intensity of immunosuppressive therapy. Whenever possible, vaccines should be administered before the onset of immunosuppression, as immune responses are typically more robust in a less compromised state. The CDC recommends that inactivated vaccines be given at least two weeks before starting immunosuppressive therapy, while live vaccines should be administered four weeks in advance if deemed safe and indicated [175]. This pre-emptive approach maximizes the likelihood of seroconversion and durable immunity.

For patients already receiving immunosuppressive therapy, vaccination should be coordinated with periods of reduced immunosuppression, such as during treatment breaks or after dose tapering, to enhance immunogenicity. Coordination between specialists—including transplant teams, oncologists, and rheumatologists—and primary care providers is essential to ensure timely and appropriate vaccine administration.

Safe and Recommended Vaccines

Non-live (inactivated, subunit, recombinant, or mRNA) vaccines are generally considered safe for immunocompromised individuals because they do not contain replicating pathogens and cannot cause vaccine-derived disease. These vaccines are strongly recommended and include:

  • Influenza (inactivated): Annual vaccination is advised for all immunocompromised patients. For high-risk groups such as solid organ transplant recipients, high-dose or adjuvanted formulations are preferred to enhance immunogenicity [176].
  • Pneumococcal vaccines: The CDC recommends sequential administration of pneumococcal conjugate vaccine 20-valent (PCV20) or pneumococcal conjugate vaccine 15-valent (PCV15) followed by pneumococcal polysaccharide vaccine 23-valent (PPSV23) at least eight weeks later, depending on prior vaccination history [157].
  • Hepatitis B: Vaccination is recommended, with post-vaccination serological testing to confirm adequate anti-HBs antibody response, as immunogenicity may be suboptimal [155].
  • Tetanus, diphtheria, and pertussis (Tdap): A single dose of Tdap is recommended, followed by Td boosters every 10 years.
  • Haemophilus influenzae type b (Hib): Recommended for patients who have not previously completed the series, particularly in the context of splenectomy or profound B-cell deficiency.
  • mRNA-based COVID-19 vaccines: Updated formulations are recommended for all immunocompromised individuals aged ≥6 months. Additional doses are advised to improve seroconversion rates, which are significantly lower than in immunocompetent individuals [179].
  • Respiratory syncytial virus vaccines: The IDSA 2025 guidelines recommend RSV vaccination for all immunocompromised adults and adolescents using approved vaccines such as Arexvy and Abrysvo [160].

Contraindications and Exceptions for Live Vaccines

Live attenuated vaccines—including measles, mumps, and rubella vaccine, varicella vaccine, zoster vaccine live, and live-attenuated influenza vaccine—are generally contraindicated in severely immunocompromised individuals due to the risk of disseminated infection [161]. However, exceptions exist based on immune reconstitution:

  • HIV-infected individuals with CD4+ T cell counts ≥200 cells/µL (or ≥15% in children) may safely receive MMR and varicella vaccines [162].
  • The recombinant zoster vaccine recombinant is preferred over the live version and is recommended for immunocompromised adults aged ≥19 years, regardless of CD4 count [163].
  • Live vaccines should be avoided in patients undergoing chemotherapy, those with severe combined immunodeficiency (SCID), and within the first two months post-transplant [184].

Special Considerations by Patient Population

HIV-Infected Individuals

Vaccination strategies for people with HIV are tailored to CD4+ count and viral suppression. Inactivated vaccines (influenza, pneumococcal, hepatitis B, COVID-19) are recommended regardless of CD4 count. Studies show that individuals on suppressive antiretroviral therapy mount robust responses to mRNA COVID-19 vaccines, supporting their safety and efficacy [185]. RZV is recommended for all PLWH aged ≥19 years.

Solid Organ Transplant Recipients

Pre-transplant vaccination is ideal. Post-transplant, inactivated vaccines are typically administered 3–6 months after transplantation, once immunosuppression is stabilized. The IDSA and transplant societies recommend updated vaccination schedules, including catch-up for missed vaccines [186]. Additional doses of mRNA COVID-19 vaccines are recommended due to suboptimal seroconversion rates (~34% after two doses) [159].

Challenges and Strategies to Enhance Vaccine Efficacy

A major challenge in vaccinating immunocompromised hosts is the attenuated immune response, which can result in reduced seroconversion and shorter duration of protection. Factors contributing to poor immunogenicity include the use of B-cell depleting agents (e.g., rituximab), high-dose corticosteroids, and profound T-cell suppression.

To address this, several strategies are employed:

  • Additional booster doses: Recommended for immunocompromised individuals to enhance and sustain protection, particularly for mRNA COVID-19 vaccines.
  • Post-vaccination serological testing: May be used in high-risk patients to assess response, although correlates of protection are not always well-defined.
  • Household and close contact vaccination: The CDC recommends vaccinating household members and close contacts to create a "cocoon" of protection against respiratory pathogens such as influenza, RSV, and SARS-CoV-2 [173].

Conclusion

Vaccination in immunocompromised hosts is essential but complex, requiring careful planning and coordination. Non-live vaccines are safe and strongly recommended, while live vaccines are generally contraindicated in severely immunocompromised individuals. Challenges include reduced immunogenicity, suboptimal timing, and the need for additional doses. Current guidelines emphasize early vaccination, use of enhanced formulations, and shared decision-making with healthcare providers. Ongoing research continues to refine strategies to improve vaccine efficacy and long-term protection in this vulnerable population [189].

Emerging Therapies and Advances in Precision Immunosuppression

The field of immunosuppression is undergoing a transformative shift from broad, non-specific immune suppression toward precision therapies that selectively target pathological immune responses while preserving protective immunity. These emerging strategies aim to overcome the major limitations of conventional immunosuppressive drugs—such as increased susceptibility to infections and malignancies—by achieving greater specificity and minimizing systemic toxicity. Advances in biologics, cellular therapies, and immune monitoring are paving the way for more effective and safer long-term management in transplantation and autoimmune diseases.

Targeted Biologics and Pathway-Specific Inhibition

Modern biologic agents represent a significant leap in precision immunosuppression by neutralizing specific cytokines or blocking key signaling pathways involved in autoimmune and inflammatory responses. Unlike traditional immunosuppressants, these agents spare protective immunity by avoiding generalized immune inhibition. For example, TNF-α inhibitors such as infliximab and adalimumab selectively disrupt pro-inflammatory cascades central to conditions like rheumatoid arthritis and inflammatory bowel disease [190]. Similarly, IL-6 receptor blockers (e.g., tocilizumab) and IL-17/IL-23 inhibitors (e.g., secukinumab, ustekinumab) are used to target specific immune axes in psoriasis and other chronic inflammatory conditions [191].

Small molecule inhibitors, such as JAK inhibitors (Jakinibs), offer another layer of selectivity by interfering with intracellular signaling downstream of multiple cytokine receptors. These agents provide a relatively selective dampening of pathogenic signaling compared to broad immunosuppressants, making them valuable in autoimmune conditions like rheumatoid arthritis [192]. Additionally, novel biologic strategies are being developed to restore immune tolerance by delivering autoantigens in tolerogenic contexts, promoting the expansion of antigen-specific regulatory T cells (Tregs) and anergy in autoreactive T cells [193].

Cellular Therapies: Engineered Immune Regulation with CAR-Tregs

One of the most promising frontiers in precision immunosuppression is the development of engineered cellular therapies, particularly chimeric antigen receptor regulatory T cells (CAR-Tregs). These therapies harness the natural regulatory functions of Tregs and direct them to sites of immune pathology using antigen-specific receptors. CAR-Tregs are designed to express a chimeric antigen receptor (CAR) that recognizes specific antigens, such as those present on allogeneic grafts or in autoimmune tissues. Upon antigen encounter, these cells localize to the target site and exert suppressive effects—through secretion of anti-inflammatory cytokines (e.g., IL-10, TGF-β), metabolic disruption, or modulation of antigen-presenting cells—without causing systemic immune suppression [194].

A key advantage of CAR-Treg therapy is the preservation of systemic immune competence. Because these cells act locally and only upon antigen recognition, patients retain the ability to defend against pathogens and respond to vaccines—a critical benefit over conventional immunosuppressive regimens [195]. In preclinical models, strategies such as transient mTOR inhibition have been shown to prevent CAR-Treg exhaustion caused by tonic signaling, thereby enhancing their therapeutic efficacy [196]. Applications are being explored in both organ transplantation, where CAR-Tregs targeting donor HLA antigens can prevent graft rejection, and in autoimmune diseases like type 1 diabetes, where CAR-Tregs directed against islet autoantigens aim to halt autoimmune destruction [197].

Synergistic and Complementary Therapeutic Approaches

Combination strategies are further refining the selectivity and durability of immunosuppressive effects. For instance, costimulation blockade combined with low-dose IL-2 therapy selectively expands and spares Tregs while inhibiting effector T cells, promoting immune tolerance in autoimmunity [198]. Similarly, Fc-engineered antibodies are being developed to differentially target immune cell subsets; for example, modified anti-CTLA-4 antibodies preferentially deplete intratumoral regulatory T cells while sparing peripheral Tregs, demonstrating how fine-tuned biologics can achieve spatial and functional selectivity [199].

Biomarker-Guided and Personalized Immunosuppression

Advances in immune monitoring are enabling real-time assessment of the "net state of immunosuppression," allowing clinicians to dynamically adjust therapy based on individual risk profiles. Non-invasive biomarkers such as donor-derived cell-free DNA (dd-cfDNA) in recipient plasma have emerged as sensitive indicators of graft injury and both T-cell-mediated and antibody-mediated rejection [43]. Elevated dd-cfDNA levels can prompt preemptive intervention before irreversible damage occurs, reducing the need for surveillance biopsies.

Gene expression profiling and blood transcriptomics provide insights into the recipient’s immune activation state, helping to distinguish between operational tolerance, stable immunosuppression, and active rejection [201]. Urinary biomarkers, such as CD8+HLA-DR+ T cells, also show promise in non-invasively predicting acute rejection [202]. Emerging technologies, including nanosensors that detect granzyme B activity—a marker of cytotoxic T-cell activation—are enabling real-time, non-invasive detection of acute rejection [203].

Pharmacogenomic testing is increasingly used to guide dosing, particularly for calcineurin inhibitors like tacrolimus. Genetic variants in CYP3A5 significantly influence drug metabolism, with expressers requiring higher doses to achieve target levels [39]. Prospective pharmacogenetic testing is being integrated into clinical protocols to reduce the risk of acute rejection or nephrotoxicity [45].

Conclusion

Emerging therapies are shifting the paradigm from broad immunosuppression to precision immune regulation. By leveraging antigen specificity, pathway selectivity, and engineered cellular control, these approaches—particularly CAR-Tregs and targeted biologics—aim to restore immune tolerance at disease sites while preserving systemic immune competence. Integration of biomarkers, immune monitoring, and pharmacogenomics enables a dynamic, patient-centered approach that balances rejection prevention with long-term safety. These advances hold promise for safer, more effective treatments in transplantation, autoimmunity, and chronic inflammatory diseases [206].

References