Cell-cell communication and regulation of effector function are pivotal in inflammation and innate immune responses, which are strictly directive by immunoglobin (Ig) superfamily receptors [1], [2]. Triggering receptor expressed on myeloid cells (TREMs) group, a set of glycosylated cell-surface specific receptors belongs to the Ig superfamily and typically expressed in the myeloid cell lineage, is involved in the regulation of various cellular crosstalk to inflammation and pathogen-induced stimuli responses [3], [4]. Till now, a gene cluster including, NCR2 (encoding NKp44), TREM1 (also known as CD354), TREML4 (TREM-like gene), TREML2, TREM2, and TREML1 genes, with low sequence homology has been identified on chromosome 6p21 loci in humans (Fig. 1) [5], [6]. Of note, no protein expression is reported for TREM-like genes while TREM-1 and TREM-2 are commonly studied for their modulatory function [4], [7]. In particular the TREM2 gene encoding TREM-2 protein, as the focus of this comprehensive review, is typically expressed on the cell-surfaces while its intracellular expression, in some cases, is also documented [8], [9]. This intracellular expression is assumed due to the trafficking of cell-surface expressed receptor into the cytoplasm by cellular phagocytic function. In this perspective, the presenilin 1 (PS1) catalytic subunit of the γ-secretase complex has been linked to the intracellular trafficking of the TREM-2 receptor in microglia [10].

Recent genome-wide association and functional assay studies have deciphered a key role of diseases-associated myeloid cell lineage in diverse pathologies, including neurodegenerative diseases (NDDs) and cancers [11], [12], [13]. In turn, high TREM-2 expression in these cells was significantly correlated to cell-specific functions, such as enhanced phagocytosis, reduced toll-like receptor (TLR)-mediated inflammatory cytokine production, increased transcription of anti-inflammatory cytokines, and reshaped T cell function [13], [14], [15], [16], [17]. On the contrary, deficiency of the TREM-2 receptor in myeloid lineage cells is substantially established with their reduced phagocytic function and enhanced proinflammatory cytokines production [18], [19], [20], [21], hence resulting in inflammatory injuries. Besides, several mutations in the TREM2 gene were identified that significantly influenced the cell-surface TREM-2 expression and distribution [22], [23]. Consequently, various produced TREM-2 variants were correlated with elevated risks of NDDs development such as Alzheimer's disease (AD), Parkinson's disease (PD), Nasu-Hakola disease (NHD), Frontotemporal lobar degeneration (FTLD), and FTLD-like syndrome [25], [26], [27], [28], [24]. Likewise, aberrant TREM-2 expression was evidently united to tumorigenesis in multiple malignancies including gliomas [29], [30], triple-negative breast cancer (TNBC) [31], [32], gastric cancer (GC) [33], [34], hepatocellular carcinoma (HCC) [35], and renal cell carcinoma (RCC) [36]. In addition, TREM-2 is characterized as an immunosuppressive receptor for modulating the tumor microenvironment (TME) [37], where it can stimulate suppressive cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) [38], [39], to prevent the anti-tumor immune responses [32].

Considering the available literature, it is convincible that TREM-2-expressing cells play a major functional role in a plethora of disease-related immune signaling hubs; thereof, the TREM-2 receptor has been projected as an important new therapeutic target [35], [40], [41]. Of interest, recent attention has been drawn to the fact that the TREM-2 receptor or its variants or isoforms exhibit complex pathways to have or gain specific functional activity, which substantially depends on the type of cells expressing it [35], [42], [43], [44], [45], [46]. However, cell-specific expression of TREM-2 can be controlled transcriptionally; for instance, by the non-coding elements, transcriptional factors, and epigenetic alterations, but also through post-transcriptional modifications available to the TREM-2 receptor in the tissue or cellular microenvironment. Notably, despite mounting evidence indicating an association between TREM-2 and various cancers, substantial aspects of TREM-2 signaling, including insights on receptor-ligand interactions and modulation of TREM-2-mediated signaling in the TME, remain inadequately understood [11], [40]. Therefore, in this review, first we have discussed the recent advances in structural biology of TREM-2 and associated ligands followed by adopted downstream signaling pathways, in particular modulating the pivotal TREM-2-dependent functions under physiological and pathological conditions. Also, we have aimed at pinpointing the cell-specific expression and molecular regulation of TREM-2 expression that can be used to advance our understanding of how to attenuate relevant diseases. Finally, we have confirmed generic TREM-2-associated functions as well as the clinical relevance of TREM-2 dysregulation in a cancer immunosuppressive environment and discussed it as a potential therapeutic target in cancer immunotherapy.