Figure 1.

Direct and indirect interaction of NK and myeloid cells in the TME and therapeutic concepts. (A) Interaction of NK and myeloid cells in the TME. NK cells can directly target tumor cells via cytolytic granules, independent of antigen recognition. Macrophages with immunostimulatory properties can independently induce tumor-cell killing through antigen presentation and production of pro-inflammatory cytokines. In the TME, myeloid cells, including TAMs, M-MDSCs, neutrophils, and PMN-MDSCs, can secrete a variety of soluble factors that inhibit NK activation and therefore suppress NK-mediated cytotoxicity. Cytokines secreted by NK cells (e.g., IFNγ, TNFα, and GM-CSF) can stimulate macrophages, driving a pro-inflammatory activated state. These two cell types can also interact at the receptor level, where myeloid cell-surface ligand and NK receptors interact, attenuating downstream signaling, e.g., NKG2D. (B) Proposed therapeutic approaches targeting myeloid-cell subsets in the TME and proposed alternative treatment sequences that can be explored to maximize immune-mediated anti-tumor response. CPI, checkpoint inhibitor. Figure created with BioRender.com.