Interleukin 18 (IL-18)

Overview

IL18 encodes interleukin-18, a pro-inflammatory cytokine of the interleukin-1 family. It is produced as an inactive precursor and becomes biologically active after proteolytic processing, classically by caspase-1 during inflammasome activation. Mature IL-18 promotes inflammatory signaling and can amplify innate and adaptive immune responses, including interferon-γ production and activation of natural killer cells and T lymphocytes. Because of these functions, IL18 is widely studied in inflammatory disease, metabolic dysfunction, tissue injury, and cancer immunology.

In biomedical research, IL-18 is often used as a readout of inflammasome activity alongside interleukin-1 beta, TNF, and Gasdermin D (GSDMD)-related pyroptosis markers. It is also explored as a therapeutic payload or immune-modulating factor in cell-based cancer strategies, including IL-18-armed CAR-T cells and engineered extracellular vesicles. Its relevance spans rheumatoid arthritis, obesity-associated metabolic disease, renal injury, neuroinflammation, skin inflammation, and antitumor immunity.

Recent Publications Summary

Recent studies have explored IL-18 as an immunostimulatory target in cancer immunotherapy, particularly in strategies designed to localize its activity to the tumor microenvironment. An anti-PD-1–IL-18 immunoconjugate (aPD1-IL18mut) was engineered by chemically linking the anti-human PD-1 antibody Lipustobart to an IL-18 variant designed to evade IL-18 binding protein. In human PD-1 transgenic mouse models, this construct was used to couple PD-1 blockade with localized IL-18-mediated immune activation, and in vitro it preserved IFN-γ secretion even under IL-18BP pressure. In MC38 tumors, the immunoconjugate promoted robust CD8+ T cell-driven tumor control, supporting the concept that IL-18 can be leveraged to enhance checkpoint inhibitor activity 42448430Jul.

IL-18 has also been incorporated into engineered cellular and vesicle-based immunotherapies. Non-activated CAR T cells engineered to secrete IL-18 were produced in a single day and showed enhanced antitumor efficacy across xenograft models of lymphoma, leukemia, and pancreatic cancer. IL-18 expression was associated with improved persistence, metabolic fitness, and resistance to exhaustion, along with increased expression of IL7R, KLF2, and MCL1 and reduced expression of inhibitory checkpoint genes such as PDCD1, TOX, and HAVCR2 41990270Apr. In a separate approach, extracellular vesicles derived from MC38 tumor cells engineered to overexpress IL-18 and/or silence TGF-β1 or IL-10 were used as an immunogenic antigen source for dendritic cell vaccines. These modified vesicles strongly stimulated dendritic cells and triggered a potent antitumor response in vitro and in vivo, with the combination of IL-18 overexpression and TGF-β1 silencing reported to be especially effective 41780683Mar.

Outside oncology, IL-18 was identified as part of inflammatory and biomarker-focused studies. In ischemic stroke, single-cell RNA sequencing and machine-learning integration highlighted Il18 as one of two hub genes in a diagnostic model, and the authors proposed Il18 as a potential early blood biomarker 42291234Jun. In a study of donkey milk exosomes in dextran sulfate sodium-induced colitis, the anti-inflammatory miRNA eca-miR-148a was reported to target NLRP3 3'UTR and suppress the NLRP3–Caspase-1–IL-18 axis, contributing to reduced disease severity and improved intestinal barrier function 42378030Jun. IL-18 was also included among serum inflammatory proteins assessed in a systematic review and meta-analysis of periodontitis, although the abstract provided does not specify the direction or magnitude of any IL-18 change 41910651Mar.

What Changes, What Holds

1. IL-18 can be redirected to intensify checkpoint blockade within tumors
NEW DIRECTION Anti-PD-1 coupling adds a localized delivery strategy to the established view of IL-18 as a pro-inflammatory immune amplifier. The new work does not overturn the baseline role of IL-18 in IFN-γ induction or antitumor immunity; instead, it suggests that the main issue is not whether IL-18 can stimulate immunity, but how to confine that stimulation to the tumor microenvironment and bypass IL-18BP restraint. The evidence is preclinical and will need broader validation before it can be treated as a generalizable immunotherapy principle 42448430Jul.

2. IL-18 is being used to improve engineered cell and vesicle therapies rather than merely serving as a readout of inflammation
NEW DIRECTION CAR T-cell secretion of IL-18 and IL-18–loaded vesicle vaccines extend the baseline’s therapeutic-interest theme, but they shift the emphasis from IL-18 as a biomarker or inflammatory mediator to IL-18 as an active design element in cell engineering. That leaves the established account intact while strengthening the idea that IL-18 can improve persistence, metabolic fitness, and antitumor function in adoptive platforms. The mixed vesicle findings also suggest that context and co-engineering matter more than IL-18 alone 41990270Apr41780683Mar.

3. IL-18 is emerging as a candidate biomarker in noncancer inflammatory disease, but its specificity remains unsettled
NEW DIRECTION Stroke and colitis studies place IL-18 in a diagnostic and mechanistic space that the Overview does not cover directly, namely early blood biomarker use and pathway-level disease stratification. That expands its relevance beyond the already established inflammatory and tissue-injury settings without contradicting them. The periodontitis meta-analysis is harder to interpret because the direction of change is not given, so it supports only continued biomarker interest, not a settled clinical signature 42291234Jun42378030Jun41910651Mar.

Overview update candidates: IL-18 as a localized immunotherapy payload in checkpoint blockade; IL-18 as an engineering component in CAR T cells and vesicle-based vaccines; IL-18 as a candidate biomarker in ischemic stroke and inflammatory disease.