Inflammation was initially recognized as an “enabling characteristic” [1] and more recently a “hallmark” [2] of cancer, and a key component of the tumor microenvironment [3], [4], [5], [6], where mechanisms of immunosuppression develop and are now identified as an emerging hallmark of cancer, named “avoiding immune destruction” [2]. Thus, inflammation acts as a tumor-intrinsic as well as a tumor-extrinsic factor in oncogenesis and tumor progression.

Inflammation in cancer is sustained by inflammatory cytokines and chemokines, among which proteins of the IL-1 family [7]. The IL-1 family is composed of IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-37, and IL-38, along with the antagonistic proteins IL-1 receptor antagonist (IL-1RA), IL-1R2, IL-R8 and IL-18bp [4], [8]. Among these cytokines, IL-1α, IL-1β, and IL-33 have shown a prominent role in cancer [9], [10], [11], [12]. They are expressed in epithelial, stromal and immune cells, and during carcinogenesis and cancer progression their expression level is regulated by genetic mutations and tissue damage- and stress-induced signals from the tumor microenvironment [13], [14].

In the tumor, IL-1α is constitutively expressed in epithelial cells, fibroblasts, endothelial cells and during inflammation is also induced in monocytes and macrophages. IL-1α can function as a transcription factor, when localized in the nucleus, as a membrane-bound cytokine, and it can be released during necrosis, as an alarmin [10], [13], [15]. IL-1β is mainly expressed in myeloid cells, more rarely in neoplastic cells, in an inactive form and it requires processing by the inflammasome to be secreted [16]. Both cytokines exert their function on multiple cell types, including epithelial cells, endothelial cells, fibroblasts but also immune cells such as natural killer (NK) cells, CD4+ and CD8+ T cells, myeloid derived suppressor cells (MDSCs), dendritic cells (DCs), and innate lymphoid cells (ILCs) [12], [13], [17].

IL-33 is constitutively expressed in the nucleus of epithelial and endothelial cells, and fibroblasts, and during inflammation its release can be induced also in smooth muscle cells, and macrophages [13], [18]. IL-33 may act as a regulator of transcription [19], [20] and, similarly to IL-1α, it may be released upon necrosis to behave as an alarmin [13]. IL-33 is implicated in tumorigenesis, metastases formation, and chemoresistance, through tumor cell intrinsic and extrinsic mechanisms (i.e., by targeting ST2 (IL-33 receptor)-expressing immune cells in the tumor microenvironment, such as regulatory T cells (Tregs), alternatively activated M2 macrophages, DCs, group 2 ILC (ILC2), NK cells, eosinophils, CD4+ and CD8+ T cells) [18].

IL-1 and IL-33 cytokines have been reported in several studies to exert both tumor-promoting and anti-tumor activity, and the mechanisms supporting these conflictual functions have been well discussed elsewhere [10], [11], [13], [21], [22], [23], [24], [25].

Here we will focus on the role of IL-1 and IL-33 in driving differentiation and/or recruitment/activation/expansion of lymphoid type-2 cells, namely CD4+ Th2 cells and ILC2s. Firstly, we will discuss the role of these two immune cell subsets in cancer and suggest that, although they may have pro- and anti-tumor functions, in most human cancers CD4+ Th2 cells are immunosuppressive, whereas ILC2s have a more conflicting role. Secondly, we will discuss the mechanisms used by the IL-1 and IL-33 cytokines to drive lymphoid type-2 cell polarization, recruitment and expansion and emerging mechanisms within the tumor microenvironment shaping dysfunctional ILC2s, and thirdly we will conclude by discussing distinct features of the two lymphoid type-2 cell subsets and translational approaches to target these cytokines/immune cell types to promote anti-tumor immunity.