Target-related Cytokines

IL-2 family cytokines are important immunoregulatory factors that control lymphocyte development, proliferation, and function. This family includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Their receptors share the common γ chain (γc, CD132) as a signaling component and primarily regulate the differentiation, survival, and effector functions of T cells, B cells, and NK cells through the JAK-STAT pathway. These cytokines play critical roles in maintaining immune homeostasis and enhancing antitumor immunity^[3].

In recent years, the IL-2 family has emerged as an important area of research in cancer immunotherapy and cell therapy. IL-2, one of the earliest cytokines used in cancer treatment, promotes the proliferation of effector T cells and NK cells. However, native IL-2 also activates regulatory T cells (Tregs) and is associated with substantial systemic toxicity. Consequently, engineered IL-2 variants, including IL-2 muteins, PEGylated IL-2, and fusion proteins, have become major areas of research and development^[4,5,6]. IL-7 supports the survival of naïve and memory T cells and contributes to immune reconstitution^[7,8]. IL-15 strongly promotes the expansion of NK cells and CD8⁺ T cells and has been widely investigated in cell therapy approaches such as CAR-T and CAR-NK therapies^[9]. IL-21 enhances the cytotoxicity of CD8⁺ T cells and NK cells and may improve the tumor immune microenvironment. With advances in cytokine engineering and targeted delivery technologies, IL-2 family cytokines are increasingly becoming an important component of cancer immunotherapy^[10,11].

The IL-12 family comprises heterodimeric cytokines including IL-12, IL-23, IL-27, IL-35, and IL-39, which play important roles in regulating both innate and adaptive immunity. IL-12 exhibits potent immune-activating and antitumor activities, but systemic administration can cause severe toxicity. Consequently, engineered delivery and localized expression have become major areas of research and development. IL-23 contributes to chronic inflammation and tumor development, and IL-23 blockade has emerged as an important immunotherapeutic strategy. IL-27 has both immune-activating and immunosuppressive functions, and its therapeutic potential remains under investigation. IL-35 primarily mediates immunosuppression and is closely associated with tumor immune evasion. Research on IL-39 remains at an early stage. Although its pro-inflammatory and pro-tumorigenic effects have been preliminarily reported, its biological functions and mechanisms of action in humans require further validation^{[18,19,20,21]}.

The IL-10 family includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, among others, and plays important roles in immune homeostasis and tissue repair. IL-10 has a well-established anti-inflammatory role; however, in cancer, it may both suppress chronic inflammation and contribute to immune evasion, resulting in context-dependent biological effects. IL-22 and IL-24 are involved in tissue repair, inflammatory regulation, and tumor-associated processes, and their signaling pathways and therapeutic potential continue to attract research interest^[22].

The interferon (IFN) family is divided into three major types: Type I, Type II, and Type III interferons. Type I interferons (IFN-α/β) exhibit antiviral and antitumor activities and have been widely used in the treatment of cancers such as melanoma and renal cell carcinoma. Type II interferon (IFN-γ) enhances antigen presentation and activates T cells and NK cells, making it an important regulator of antitumor immunity. Type III interferons primarily act on epithelial tissues and participate in mucosal antiviral defense. Their relatively restricted receptor distribution may provide potential therapeutic advantages^[23,24].

The TNF family is an important group of immunoregulatory cytokines that includes TNF-α, TRAIL, FasL, CD40L, BAFF, APRIL, RANKL, and other members. By binding to members of the TNF receptor (TNFR) superfamily, these cytokines activate signaling pathways including NF-κB, MAPK, and caspases, thereby regulating inflammation, apoptosis, immune cell activation, and tissue homeostasis. TNF family members can promote antitumor immunity but may also contribute to chronic inflammation and tumor immune evasion, making them important therapeutic targets in cancer and autoimmune diseases. Therapeutic agents and immunotherapeutic strategies targeting TNF-α, CD40L, TRAIL, and other TNF family members continue to advance[25]. (To explore more content on the TNF family, please visit the TNF family topic page.)