Furthermore, tumor-associated macrophages (TAMs) contribute to the development of a pro-tumorigenic microenvironment that fosters resistance to MAPKi therapy by providing an abundance of oxygen, nutrients (resulting in hypoxia and metabolic stress), and extracellular matrix proteins.466 Subsequently, TAMs secrete angiotensin, COX-2, IFN, and IL-1, further promoting the growth and metastasis of melanoma.467 Thus, to enhance the effectiveness of combination therapy for melanoma patients, targeting spatiotemporal interactions within tumor microenvironments holds significant promise. This evidence concerns the gene PTGS2 and melanoma.