(A) Macrophage differentiation is highly heterogenous and depends mostly on the environmental cues within their niche. The classical binary division includes the M1 (tumoricidal and pro-inflammatory) and M2 (tumor-supporting and antiinflammatory) polarization. The increasingly favored macrophage division considers macrophage diversity as a spectrum and includes tumor-associated macrophages (TAMs), alveolar macrophages (AMs), and interstitial macrophages (IMs) as separate subtypes with mostly pro-tumor properties in LC/NSCLC. The dynamic macrophage-tumor crosstalk within the TME results in different activation of the immune cells and confers a range of effects that can either aid the tumor development and progression or halt it. The included differentiation factors are the most represented within the existing literature. A range of other cues were found to contribute to macrophage differentiation but their effect is not yet well defined. The red and orange boxes mark all the macrophage subtypes that are generally considered pro-tumorigenic in LC/NSCLC settings and their associated effects on tumor cells (and vice versa). IL, interleukin; GM-CSF, granulocyte macrophage colony-stimulating factor; TGF, transforming growth factor; GCs, glucocorticoids; IFN, interferon; LPS, lipopolysaccharides. (B) The prognosis and survival of NSCLC patients are reflected by the macrophage infiltrate within the tumor islets. Greater M1 infiltrate generally indicates a favorable prognosis, while the predominance of M2 predicts reduced survival.
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