Targeting myeloid cell immunometabolism to improve current non-small cell lung cancer therapies

Abstract

Although recent advancements in immunotherapy have improved clinical outcomes, non-small cell lung cancer (NSCLC) is still the deadliest cancer type, as current treatments fail in many patients. This highlights a need for continued studies on this complex and multifaceted malignancy. The lung tumor microenvironment (TME) is marked by an infiltration of innate immune cells of the myeloid lineage, including macrophages and neutrophils, which affect patient outcomes. These cells induce inflammation and functional responses that can both promote and inhibit tumor growth and progression, with these functions being directly linked to their intracellular metabolism. The lung TME provides a milieu of signals, including cytokines and metabolites, that induce metabolic reprogramming in tumor-associated myeloid cells. Here, we review the present understanding of tumor-associated myeloid cell metabolism specifically in the context of NSCLC. Recent studies demonstrated that some metabolic pathways have the potential to be manipulated pharmacologically to eliminate or reprogram pathogenic, pro-tumor, and/or immunosuppressive myeloid cells to anti-tumor states for NSCLC therapies. Therefore, we highlight and propose potential metabolic targets in these myeloid cells, focusing on macrophages and neutrophils. These cells have direct roles in affecting subsequent responses of adaptive cells and their cellular metabolism must be further investigated to identify potential pharmacologic therapeutic targets. Targeting myeloid cell metabolism in the TME may be used in combination with the current regimen of immune checkpoint inhibition (ICI) and chemotherapy to improve outcomes for lung cancer patients.