The collaboration of immunology and oncology for cancer treatment has experienced revolutionary development during the recent decades. Modern immunotherapy approaches have significantly improved the treatment of advanced malignancies [1], [2]. However, the clinical effectiveness of cancer immunotherapy techniques is limited by the immunosuppressive milieu of the tumor microenvironment (TME), which is a characteristic of most malignancies [3]. The immune characteristics of the TME play a decisive role in predicting the clinical outcomes of patients [4], [5]. It is widely understood that all immunotherapies and most traditional anticancer treatments exert their therapeutic effects by modulation of pre-existing immune responses [6]. Thus, it seems that the next crucial step in maximizing the efficacy of current immunotherapies is priming the tumor immune microenvironment (TIME) to address the tumor immunosuppressive microenvironment [7], [8]. Local production or administration of immunestimulating factors, such as cytokines, can counteract the immunosuppressive dilemma [9].

Cytokines are the first modern immunotherapeutic agents used for activation immunotherapy to alter the immunosuppressive environment of the TME, induce long-lasting immune responses, and enhance the immune system to eliminate tumor cells [10], [11]. The therapeutic efficacy of several cytokines for boosting anticancer immune responses has been demonstrated in preclinical studies [12]. Two cytokines have so far been approved by the FDA as monotherapy for cancer immunotherapy: IL-2 for metastatic melanoma and renal cell carcinoma and interferon-α for stage III melanoma [11].

Over the past three decades, IL-18 has been introduced as an immune-enhancing cytokine. It has been demonstrated that IL-18 promotes both the differentiation of naïve CD4+ T lymphocytes into Th1 cells and the development of memory cytotoxic CD8+ T lymphocytes [13], [14]. IL-18 can increase immunoglobulin production and antibody-dependent cellular cytotoxicity (ADCC) through activation of B lymphocytes [15], [16], [17]. IL-18 is involved in the activation of IL-17–producing γδ T cells, Th2, and macrophages [18]. Through the CD134 costimulatory pathway, IL-18 bridges the adaptive and innate immune systems [19]. It promotes the activation of NK cells and increases their cytotoxic function [20], [21]. IL-18 enhances the expression of Fas ligand on NK cells, which promotes the process of apoptosis or induces cell death [15], [22], [23], [24]. Furthermore, IL-18 can cooperate with some cytotoxic drugs, such as doxorubicin, paclitaxel, topotecan, carboplatin, and gemcitabine to enhance their anti-tumor potency [25], [26]. These features encourage the application of IL-18 as an adjuvant or immunotherapeutic agent to alter the immunosuppressive atmosphere of the TME.

Although several preclinical studies have shown the potential of IL-18 as an immunotherapeutic agent, clinical trials using IL-18 as a single therapeutic agent have reported disappointing results. However, given the potential of IL-18, researchers continue to improve it and consider new roles for it in the modern immunotherapy era [12]. In this study, we comprehensively reviewed the potential of IL-18 as a biological adjuvant and cancer immunotherapy agent and, critically discussed the weaknesses of this cytokine that may have reduced its effectiveness in clinical studies. Next, we reviewed novel bioengineering strategies that have shown promise in addressing the weaknesses of this cytokine. Finally, the potential of IL-18 for improving the capabilities of modern cell-based cancer immunotherapy approaches is described to provide a perspective for future research and pave the way for the clinical applications of this potent cytokine.