Cytokine activity within the tumor microenvironment plays a crucial role in shaping how innate and adaptive immune cells interact and determine the fate of tumor progression (Balkwill, Capasso, & Hagemann, 2012). In this environment, dysregulated cytokine production by tumor and immune cells is a hallmark of cancer (Awasthi et al., 2007, Aghayev et al., 2022). Cytokines act as critical regulators of inflammatory cell function, orchestrating immune responses by recruiting, activating, or suppressing immune cells and modulating cellular growth and specialization (Berraondo et al., 2019).

Among these cytokines, IL-27, a member of the IL-12 family, has demonstrated remarkable antitumor effects in various cancer models, positioning it as a promising candidate for cancer immunotherapy studies (Batten et al., 2008, Batlle and Massague, 2019, Beadling and Slifka, 2006, Burke and Young, 2019, Berraondo et al., 2019). IL-27 is key in regulating innate and adaptive antitumor immunity, driving antitumor effects through multiple mechanisms tailored to individual tumor characteristics. It stimulates the generation of cytotoxic T cells (CTLs) and the differentiation of CD4+ T cells. Moreover, it activates innate effectors such as natural killer (NK) cells and T cells, thereby increasing cytolytic activity and cytokine production. IL-27 enhances immunoglobulin class switching in B cells and can directly influence specific tumor cells. However, The role of IL-27 is complex, and it performs diverse functions that balance immune-enhancing and immune-regulatory effects (Carbotti et al., 2015, Chiba et al., 2018), such as the polarization of effector CD4+ T cells into regulatory T cells (Tregs) (Park et al., 2019), induction of IL-10 (Awasthi et al., 2007), the inhibition of B cell differentiation, and the suppression of inflammatory cytokines (Bin Dhuban et al., 2019, Chiba et al., 2018). This role of IL-27 in pleitropism can be context dependent (Hall, Beiting, Tato, John, Oldenhove, Lombana et al., 2012). The balance and precise regulation of IL-27 signaling are therefore important for proper antitumor immune function in cancer.

In this chapter, we delve into the dual role of IL-27 in immune regulation and cancer, exploring its functional nuances and similarities for optimal use in immunotherapy strategies against tumors.