Interleukin-2 (IL2): The "Double-Edged Sword" of the Immune System

2. Research Mechanism

The biological functions of IL2 depend on its binding to the IL2 receptor (IL2R), with effects that are dose-dependent and cell type-specific, as detailed below:

2.1 IL2 Receptor Subtypes and Functional Differences

The IL2R is composed of CD25 (α-chain), CD122 (β-chain), and CD132 (γ-chain), forming three types of receptors through different combinations:

2.1.1 High-affinity receptor (CD25+CD122+CD132)

Expressed only on Treg cells, this receptor has the highest affinity for IL2 (Kd≈10⁻¹¹ M). Low-dose IL2 (e.g., 0.3-1×10⁶ IU/m²) can continuously activate Treg cells through this receptor, promoting their proliferation, survival, and functional maintenance (e.g., stable expression of FOXP3) ^[4,5]. For example, in patients with chronic graft-versus-host disease (GVHD), after 4 weeks of low-dose IL2 treatment, the number of Treg cells increased more than 8-fold compared to baseline, and the proportion of FOXP3+ cells significantly increased ^[4].

2.1.2 Medium-affinity receptor (CD122+CD132)

Expressed on Teff, NK cells, and memory T cells, this receptor has moderate affinity (Kd≈10⁻⁹ M). High-dose IL2 (e.g., 600,000-720,000 IU/kg) preferentially activates this receptor, enhancing the expression of cytotoxic molecules (such as perforin and granzymes) and thereby increasing the antitumor/anti-infection activity of Teff and NK cells ^[3,7].

2.1.3 Low-affinity receptor (CD122+CD132, without CD25)

With the lowest affinity (Kd≈10⁻⁷ M), this receptor mainly functions in the later stages of immune activation, participating in the formation of immunological memory ^[1].

2.2 Dose-Dependent Immune Modulatory Effects

2.2.1 Immune activation by high-dose IL2 (HD-IL2)

• Stimulates the proliferation and differentiation of Teff cells: Enhancing their recognition and killing of tumor cells. In melanoma research, the combination of HD-IL2 and gp100 vaccine increased the number of antigen-specific CD8+ T cells, raising the objective response rate (ORR) from 6% to 16% ^[3].
• Activates NK cells: HD-IL2 promotes the secretion of IFN-γ by NK cells, enhancing their antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. For example, in a neuroblastoma model, the combination of IL2 and anti-GD2 antibody significantly increased the cytotoxic activity of NK cells against tumor cells ^[8].

2.2.2 Immune suppression by low-dose IL2:

• Selectively expands Treg cells: By maintaining the expression of FOXP3 and inhibitory functions of Treg cells, it reduces excessive immune responses. In HCV-induced vasculitis, low-dose IL2 increased the proportion of Treg cells among CD4+ T cells from 5% to 15% at baseline, while inhibiting the secretion of pro-inflammatory cytokines (such as IL-17 and TNF-α) ^[9,10].
• Regulates immune balance: By increasing the Treg:Tcon (conventional T cell) ratio (from 0.07 to 0.39), it inhibits the activation of autoreactive T cells. In patients with chronic GVHD, an elevated ratio was significantly associated with the improvement of symptoms such as skin sclerosis and liver dysfunction ^[4].

2.3 Synergistic Mechanisms with Other Molecules

• Combination with vaccines: The gp100 peptide vaccine activates antigen-specific T cells, while IL2 provides co-stimulatory signals to promote their proliferation. The combination extended the median overall survival of melanoma patients from 11.1 months to 17.8 months ^[3].
• Combination with HDAC inhibitors: Entinostat inhibits the immunosuppressive functions of Treg cells (e.g., reducing IL-10 secretion). When combined with HD-IL2, the ORR in mRCC patients increased from 20-25% to 37%, and the median progression-free survival (PFS) extended from 4.2 months to 13.6 months ^[2].
• Combination with immune checkpoint inhibitors: Low-dose ipilimumab (anti-CTLA-4) can relieve the immunosuppression of T cells and, in combination with HD-IL2, synergistically activate Teff cells. This has achieved an objective response rate (ORR) of 18.2% in immune-resistant melanoma, with some patients experiencing durable responses lasting over 37 months ^[7].

3. Signal Pathways

IL2 activates specific signaling pathways through binding to different types of receptors, with effects significantly varying depending on cell type and IL2 dose:

3.1 JAK-STAT Pathway (Primarily Regulates Treg Function)

When IL2 binds to the high-affinity receptor (CD25+CD122+CD132), it recruits and activates JAK1 and JAK3 kinases, leading to the phosphorylation of STAT5 and the formation of dimers that enter the nucleus to regulate the expression of genes such as FOXP3 and CD25. This is the core pathway for maintaining the survival, proliferation, and function of Treg cells ^[8,15]. Low-dose IL2 preferentially activates this pathway. In patients with chronic GVHD, after 4 weeks of treatment, the expression of FOXP3 in Treg cells increased 2.3-fold compared to baseline and was maintained with continued treatment ^[4].

3.2 PI3K-Akt Pathway (Primarily Regulates Cell Proliferation and Survival)

This pathway is mainly mediated by the medium-affinity receptor (CD122+CD132). After IL2 binds, it activates PI3K through Src family kinases, generating PIP3 and recruiting Akt for phosphorylation. This process inhibits pro-apoptotic molecules (such as Bad) and activates proliferation-related genes (such as Cyclin D1), ultimately promoting the survival and proliferation of Teff and NK cells ^[1]. In melanoma treatment, high-dose IL2 increased the level of phosphorylated Akt in Teff cells by 1.8-fold and the proliferation index (Ki67+) by 40%, directly enhancing the antitumor immune response ^[3].

3.3 MAPK Pathway (Auxiliary Regulation of Immune Cell Activation)

IL2 activates this pathway through the Ras-Raf-MEK-ERK cascade, especially significantly in Teff cells treated with high-dose IL2. After ERK is phosphorylated and enters the nucleus, it promotes the transcription of cytokines such as IL-2 and IFN-γ, enhancing the cytotoxic function of effector T cells ^[1]. For example, in the treatment combining gp100 vaccine and IL2, the secretion of IFN-γ by Teff cells increased 2.1-fold compared to the IL2 monotherapy group, directly correlating with enhanced tumor-killing activity ^[3].

3.4 Cross-Regulation of Pathways

The balance between the JAK-STAT and PI3K-Akt pathways determines the direction of the immune response: low-dose IL2 preferentially activates the JAK-STAT pathway (Treg dominant), while high-dose IL2 simultaneously activates the PI3K-Akt pathway (Teff dominant) ^[1]. Additionally, STAT5 activated by IL2 can synergize with the NF-κB pathway in NK cells to upregulate the expression of cytotoxic molecules such as perforin, further enhancing immune effects ^[8].

4. Related Diseases

Abnormal regulation of IL2 can lead to immune imbalance and disordered signaling pathways, which are closely related to the occurrence and development of various diseases:

4.1 Malignant Tumors

4.1.1 Renal Cell Carcinoma (RCC)

Weakening of IL2 signaling in the tumor microenvironment is an important mechanism for immune evasion in RCC. Tumor cells can secrete inhibitory factors such as IL-10, downregulating the expression of CD122 on T cells, thereby reducing the sensitivity of Teff cells to IL2 and weakening the antitumor immune response ^[2,11]. The ORR of HD-IL2 monotherapy for metastatic clear cell RCC is 20-25%, with a median PFS of 4.2 months. However, patients who achieve complete remission can have a survival period of over 5 years. When combined with entinostat, the ORR increases to 37%, and the median PFS extends to 13.6 months. This is because entinostat can reverse the immunosuppressive function of Treg cells and enhance the activation of Teff cells by IL2 ^[2,11].

4.1.2 Melanoma

Some melanoma cells inhibit the expression of IL2 pathway-related genes (such as JAK3 and STAT5) through mutations or epigenetic modifications, blocking the proliferation of Teff cells. Meanwhile, tumor-infiltrating Treg cells highly express CD25, competitively binding IL2 and further weakening the immune response ^[3,7]. The ORR of HD-IL2 combined with gp100 peptide vaccine in HLA-A0201-positive patients is 16%, higher than the 6% achieved with HD-IL2 monotherapy. This is because the antigen-specific T cells activated by the vaccine are more responsive to the proliferative signals of IL2. For immune-resistant patients, the ORR of HD-IL2 combined with low-dose ipilimumab and nivolumab is 18.2%. This is because checkpoint inhibitors can release the “brakes” on T cells, and in combination with IL2, synergistically restore antitumor activity ^[3,7].

4.1.3 Neuroblastoma

Neuroblastoma cells highly express the GD2 antigen on their surface, but the IL2 concentration in their microenvironment is insufficient, limiting the ADCC effect of NK cells ^[8]. The combination of dinutuximab, IL2, and GM-CSF can enhance the ADCC effect of NK cells. However, the SIOPEN trial showed that compared to dinutuximab alone, the addition of IL2 did not significantly improve the 3-year event-free survival rate (56% vs. 60%), and the incidence of grade 3-4 capillary leak syndrome was higher (11-13% vs. 3-6%). This may be due to the excessive activation of monocytes by IL2, leading to the release of inflammatory cytokines ^[8].

4.2 Autoimmune and Transplant-Related Diseases

4.2.1 Chronic Graft-Versus-Host Disease (GVHD)

After allogeneic hematopoietic stem cell transplantation, donor-derived Teff cells attack host tissues due to IL2 signal hyperactivity. Meanwhile, Treg cells have defects in number or function (such as unstable FOXP3 expression) and cannot effectively suppress excessive immunity ^[4]. For patients refractory to glucocorticoids, daily subcutaneous injection of IL2 (1×10⁶ IU/m²) for 8 weeks resulted in partial remission in 52% of patients. This is because IL2 preferentially expands Treg cells, increasing the Treg:Tcon ratio from 0.07 to 0.39 and restoring immune balance ^[4].

4.2.2 HCV-Induced Vasculitis

HCV infection induces B cells to produce cryoglobulin, activating the complement system and neutrophils. Meanwhile, Treg cells are impaired in function (reduced activity of the IL2-JAK-STAT5 pathway), leading to the overactivation of autoreactive T cells ^[9,10]. After treatment with IL2 in 10 patients, 8 showed symptom improvement. This is because IL2 enhanced the expression of FOXP3 and inhibitory functions of Treg cells, reducing the expression of inflammatory genes (TNF-α, IL-6) ^[9,10].

4.2.3 Multiple Sclerosis (MS)

In MS patients, T cells infiltrating the central nervous system have abnormally elevated sensitivity to IL2 and proliferate excessively through the PI3K-Akt pathway. Meanwhile, NK cells have impaired function due to insufficient IL2 supply and cannot clear autoreactive T cells ^[12]. The anti-CD25 antibody (daclizumab) can block the binding of IL2 to Treg cells, allowing free IL2 to preferentially activate NK cells and reduce T cell infiltration. s have shown that it reduces the annual relapse rate from 0.46 to 0.21 ^[12].

4.3 Infectious Diseases

4.3.1 HIV Infection

HIV targets and destroys CD4+ T cells, leading to reduced IL2 secretion. Meanwhile, viral proteins (such as Nef) can interfere with the assembly of IL2R, weakening the response of remaining CD4+ T cells to IL2 and impeding immune reconstitution ^[13]. IL2 can promote the proliferation of CD4+ T cells. However, the INSIGHT-ESPRIT trial showed that IL2 combined with antiretroviral therapy did not reduce the risk of opportunistic infections or death. Only in the subgroup with baseline CD4+ T cell counts < 200/μL did IL2 treatment reduce the primary endpoint events by 22%, as these low-level CD4+ T cells are more dependent on IL2 for recovery ^[13].

5. Recent Research Advances in IL-2-Related Drugs

Recently, significant progress has been made in the development of IL-2-related drugs. Rezpegaldesleukin, developed by Nektar Therapeutics, has successfully completed a Phase 2b for the treatment of moderate to severe atopic dermatitis, significantly reducing the Eczema Area and Severity Index (EASI) with good safety. Teva and Fosun Pharma have partnered to jointly develop TEV-56278, an immunotherapy that fuses an anti-PD-1 antibody with IL-2, aiming to enhance antitumor activity while reducing toxicity. Asher Bio's IL-2 candidate drug AB248 is also undergoing Phase 1a/1b s for the treatment of various advanced solid tumors and is planned to be combined with bispecific T cell engagers for small cell lung cancer. Additionally, several IL-2 drugs are in preclinical or clinical research stages, some of which are listed below:

*Data sourced from Patsnap

6. CUSABIO IL-2 Related Product Recommendations