The tumor microenvironment (TME) not only facilitates cancer progression from the early formation to distant metastasis, but also it differs itself from time to time alongside the tumor evolution. Tumor-associated macrophages (TAMs), whether as pre-existing tissue-resident macrophages or recruited monocytes, are an inseparable part of this microenvironment. As their parents are broadly classified into a dichotomic, simplistic M1 and M2 subtypes, TAMs also exert paradoxical and diverse phenotypes as they are settled in different regions of TME and receive different microenvironmental signals. Briefly, M1 macrophages induce an inflammatory precancerous niche and flame the early oncogenic mutations, whereas their M2 counterparts are reprogrammed to release various growth factors and providing an immunosuppressive state in TME as long as abetting hypoxic cancer cells to set up a new vasculature. Further, they mediate stromal micro-invasion and co-migrate with invasive cancer cells to invade the vascular wall and neural sheath, while another subtype of TAMs prepares suitable niches much earlier than metastatic cells arrive at the target tissues. Accordingly, at the neoplastic transformation, during the benign-to-malignant transition and through the metastatic cascade, macrophages are involved in shaping the primary, micro-invasive and pre-metastatic TMEs. Whether their behavioral plasticity is derived from distinct genotypes or is fueled by microenvironmental cues, it could define these cells as remarkably interesting therapeutic targets.

Fibromyalgia (FM) with a global incidence of 2.7%-4.7%, is a poorly understood condition of widespread pain, fatigue, multiple somatic symptoms, and associated comorbidities. 1,2 Accumulating data suggest that FM incurs a high clinical and economic burden on both patients and societies, comparable with other chronic diseases such as diabetes and hypertension. The substantial burden of this condition may be caused by several factors, such as the exhausting challenges in diagnosis and management of patients, presence of various comorbidities, low quality of life, and marked social invalidation. 3,4 Patients with FM often have a long journey to correct diagnosis and management. They undergo multiple visits, numerous investigations, and treatments, even after being diagnosed with FM, mainly because of the patient's and physician's dissatisfaction with their consultations. There is no reference standard of diagnosis or

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