Macrophages comprise a heterogeneous and functionally versatile population of innate immune cells [1,2,3]. Every adult tissue contains an abundant population of macrophages either as resident cells or monocyte-derived cells that play tissue-specific functions and are essential for organ homeostasis [4,5,6]. Tissue-resident macrophages (TRMs) are long-lived cells and can be phenotypically distinct from monocyte-derived macrophages (MDMs). Initially, it was believed that TRMs in an adult are maintained by a constant replenishment of bone marrow-derived circulating monocytes in the steady state. This model was based on the assumption that terminally differentiated macrophages were unable to enter the cell cycle [7]. This was refuted by strong evidence that differentiated macrophages in several tissues were derived from precursors in yolk sac or fetal liver, independently of bone marrow, and self-maintained throughout life by local proliferation [8,9,10,11]. Accordingly, mature macrophages can proliferate in response to specific stimuli indefinitely and can also be expanded and maintained in long-term culture without loss of differentiation [12]. These findings demonstrated that macrophages exhibit a self-renewal potential similar to that of stem cells [12,13]. Distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal capacity in both stem and mature cells. In particular, single cell analyses identified key transcription factors, e.g., c-myelocytomatosis (c-Myc), Krüppel-like factor 2 (KLF2) and Krüppel-like factor 4 (KLF4), involved in macrophage self-renewal [14]. Conversely, MafB and c-Maf repress the self-renewal of resident macrophages [14,15]. Moreover, several in vivo studies have demonstrated that bone marrow-derived monocytes can also differentiate into self-renewing tissue-resident macrophages [16,17,18,19]. Similar to embryo-derived macrophages, KLF2 was strongly upregulated in the self-renewing bone marrow-derived macrophages. This was accompanied by the downregulation of MafB, unravelling a molecular mechanism of proliferation amongst self-renewing macrophages of different origins [13].

The discovery that TRMs were capable of self-renewal led to the new concept that macrophage proliferation played a key role in the expansion of macrophage populations in the TME, which is composed of the stroma and the tumor cells. During tumor growth, both TRMs and newly recruited monocyte-derived macrophages can give rise to TAMs which have been correlated with poor clinical outcome in most cancers [20,21,22,23,24,25,26]. Emerging evidence showed that TAMs retained the self-renewal capacity [23,25,27,28,29,30]. This unique feature was shown to markedly contribute to increasing the pool of protumoral TAMs, whether they derive from the yolk sac or the bone marrow, in mammary [23] and pancreatic [25] tumors.

High plasticity is a characteristic feature of macrophages that enables them to rapidly change phenotypes in response to environmental cues [31]. One of the best examples is the macrophage adaptation to the tumor environment, which has commonly been discussed in terms of a spectrum of polarization states from anti-tumor M1 to protumor M2 phenotypes [32]. Macrophage plasticity also concerns their metabolism and its modulation has emerged as a key factor in controlling macrophage activation and functions [33,34,35]. Although metabolic plasticity is associated with and participates to macrophage polarization state [36], it is becoming clear that specific metabolic signatures have an impact on self-renewing macrophages.

2. Macrophages Proliferation in Health and Disease