Runtsch Marah C, Angiari Stefano, Kargl Julia
Division of Pharmacology, Otto Loewi Research Institute, Medical University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria; Clinical Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Division of Immunology, Otto Loewi Research Institute, Medical University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria.
Pharmacol Ther. 2025 Sep;273:108893. doi: 10.1016/j.pharmthera.2025.108893. Epub 2025 Jun 4.
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.
尽管免疫疗法的最新进展改善了临床疗效，但非小细胞肺癌（NSCLC）仍是最致命的癌症类型，因为目前的治疗方法在许多患者中失败。这凸显了对这种复杂且多方面的恶性肿瘤持续进行研究的必要性。肺肿瘤微环境（TME）的特征是髓系先天免疫细胞浸润，包括巨噬细胞和中性粒细胞，这些细胞会影响患者的预后。这些细胞诱导炎症和功能反应，既能促进也能抑制肿瘤生长和进展，这些功能直接与其细胞内代谢相关。肺TME提供了包括细胞因子和代谢产物在内的信号环境，可诱导肿瘤相关髓系细胞发生代谢重编程。在此，我们综述目前对肿瘤相关髓系细胞代谢的理解，特别是在NSCLC背景下。最近的研究表明，一些代谢途径有可能通过药物进行调控，以消除或重编程致病性、促肿瘤和/或免疫抑制性髓系细胞，使其转变为抗肿瘤状态用于NSCLC治疗。因此，我们着重介绍并提出这些髓系细胞中的潜在代谢靶点，重点关注巨噬细胞和中性粒细胞。这些细胞在影响适应性细胞的后续反应中具有直接作用，其细胞代谢必须进一步研究以确定潜在的药物治疗靶点。靶向TME中髓系细胞的代谢可能与当前的免疫检查点抑制（ICI）和化疗方案联合使用，以改善肺癌患者的预后。
