Immunosuppressive myeloid cells are recognized as a key barrier for cancer immunotherapy. Using an integrated technology for single-cell RNA-sequencing and intracellular protein measurements, A recent paper published in Cell provides evidence that TREM2 was identified as a marker for tumor-associated macrophages (TAMs) and monocytes. 1 Immune checkpoint inhibitors (ICIs) targeting CTLA-4 or PD-1/PD-L1 have contributed to improve clinical outcomes in some types of malignancies. However, a substantial proportion of patients show limited clinical benefits following ICI therapy. While tumor-intrinsic factors, such as tumor mutational burden, have been recognized as a key determinant for therapeutic responsiveness to ICIs, the immunosuppressive tumor microenvironment (TME) also critically contributes to therapeutic resistance by limiting the tumor infiltration and activation of effector lymphocytes. In this context, targeting tumor-infiltrating myeloid cells such as TAMs and myeloid-derived suppressor cells might be a rational approach to harness antitumor immunity, given their potent immunosuppressive activities and abundance in the TME. However, due to the heterogeneity of immunosuppressive myeloid cells, it is often challenging to design myeloid-directed immunotherapy. 2 A recent paper published in Cell provides evidence that TREM2 (Triggering-Receptor-Expressed on Myeloid cells 2)-expressing myeloid subsets are key regulators of antitumor immunity. 1

TREM2 is a member of the Ig-superfamily that transmits activation signaling via an adaptor protein DAP12. 3 The functional and pathological significance of the TREM2 receptor is best demonstrated in the context of AlzheimerLs disease (AD), as lossof-function variants in TREM2 are associated with an increased risk of AD. 3 TREM2 expressed on microglia cells play a critical role for maintaining metabolic fitness during physiological stress by sensing multiple ligands such as lipids, lipoproteins, and oligomeric amyloid-β, which contribute to modulate AD-associated neuropathology. 3 In addition to microglia, the expression of TREM2 is observed in tissue-resident macrophages, such as macrophages in the hair follicle stem cell niche, adipose tissues, and bone (osteoclast). 3 However, it remained largely unknown whether TREM2 was important in myeloid immunosuppression in the TME.